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2017-10-25T23:21:13Z

Z5076158:

2017 Group Project 6

2017-10-24T23:56:07Z

Z5076158:

{{ANAT2341Project2017header}}

='''Cerebellum'''=

=Introduction=
The cerebellum is a large portion of the brain that functions in coordination, balance and control, and its development occurs both prenatally and postnatally. The cerebellum underlies the occipital and temporal lobes of the cerebral cortex and constitutes to about 10% of the brains weight however contains around 50% of the neurons.
This page will highlight the anatomy of the cerebellum, its developmental process, current research on the structure, animal models and abnormalities associated with it. The anatomy will discuss the distinguishable lobes and zones of the cerebellum. The anatomy of the cerebellum cannot be completely discussed without explaining the vasculature of the structure and hence this page will provide a brief overview of it. The development of the cerebellum discusses the neural development and where the cerebellum forms on the neural tube. The development will highlight how the circuitry of the post-natal cerebellum came to be from neurons. Hence purkinje cells, granule cells, deep nuclei cells, glia cells and cerebellar nuclei will be highlighted to discuss the developmental process. A developmental timeline of the formation of the cerebellum is also included on this page. The cerebellum is a topic of continuous research and past findings would not have been done without the use of animal models, hence current research and animal models will be discussed. The abnormalities that could happen if the cerebellum were to be affected is also highlighted.

=Basic Anatomy of the Cerebellum=

The cerebellum has 3 distinguishable lobes; flocculonodular lobe, anterior lobe and the posterior lobe. The anterior and posterior lobe can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres (Figure 1)
<ref name=”PMID9735944”><pubmed> 9735944</pubmed></ref>. In a superior cerebellar view, the cerebellum contains a vermis that runs through the middle of the organ and 2 intermediate zones located laterally from the vermis (Figure 2).

[[File:Anatomical-Lobes-of-the-Cerebellum.jpg|500px]]

'''Figure 1:''' Anatomical lobes observed in the cerebellum; anterior lobe, posterior lobe and flocculonodular lobe, which is divided by two fissures – the primary fissure and posterolateral fissure <ref name="Venturini, S. (2017, October 21). The Cerebellum. Retrieved October 23, 2017, from http://teachmeanatomy.info/neuro/structures/cerebellum/">Venturini, S. (2017, October 21). The Cerebellum. Retrieved October 23, 2017, from http://teachmeanatomy.info/neuro/structures/cerebellum/</ref>

[[File:Cerebellum anatomical subdivisions.png|500px]]

'''Figure 2:''' Superior view of the 3 cerebellar zones. The middle is the vermis. Either side of the vermis is the intermediate zone. Lateral to the intermediate zone is the lateral hemispheres. There is no difference in gross structure between the lateral hemispheres and intermediate zones. <ref>File:CerebellumDiv.png. (2016, December 15). Wikimedia Commons, the free media repository. Retrieved 12:48, October 24, 2017 from https://commons.wikimedia.org/w/index.php?title=File:CerebellumDiv.png&oldid=226277429.</ref>

[[File:Arteries of the cerebellum.jpeg|thumb|'''Figure 3:''' Diagram of the main arteries of the cerebellum <ref name="Venturini, S. (2017, October 21). The Cerebellum. Retrieved October 23, 2017, from http://teachmeanatomy.info/neuro/structures/cerebellum/"/>]]

==Vasculature==
The cerebellum contains 3 bilateral paired arteries which supplies this organ with oxygenated blood. These arteries all originate from the vertebrobasilar system; Superior Cerebellar Artery (SCA), Anterior Inferior Cerebellar Artery (AICA) and the Posterior inferior cerebellar artery (PICA). The SCA and AICA are branches of the basilar artery, which wraps around the anterior aspect of the pons before reaching the cerebellum. The PICA arises from the left and right vertebral artery, which form the basilar artery <ref>The Blood Supply of the Brain and Spinal Cord. (2001). In D. Purves, G. Augustine, & D. Fitzpatrick (Eds.), Neuroscience (2nd ed.). Sunderland, MA: Sinauer Associates.</ref>. The PICA and AICA combine to supply the inferior half of the cerebellum, while the SCA supplies the majority of the superior half. The PICA and SCA combine to supply the vermis<ref name=”PMID2535662”><pubmed> 2535662</pubmed></ref>. Blood is then drained by superior and inferior cerebellar veins into the superior petrosal and then straight dural venous sinuses. (Figure 3) <ref name=”PMID27766499”><pubmed> 27766499</pubmed></ref>

==Ectoderm==

There are 3 germ layers present in the early embryo; ectoderm (most distal layer), mesoderm (middle layer) and endoderm (most proximal layer). The ectoderm differentiates into the nervous system, forming the spine, peripheral nerves, cerebrum and cerebellum. It also differentiates to form tooth enamel, epidermis, and the linings of the mouth, anus, sweat glands and nostrils<ref name=”PMID14550785”><pubmed> 14550785</pubmed></ref>.

==Microanatomy==
===Cortical Layers===
[[File:Screen Shot 2017-10-16 at 1.43.55 pm.png|thumb|'''Figure 4:''' (A). Cell types and where they are found in the cerebellar cortical layers. (B) Shows how the different layers of the cerebellum can be easily determined. P - the Purkinje layer; G - the granular layer; M - the molecular layer; W - the white matter. <ref><pubmed>3527225</pubmed></ref> ]]
There are 3 major cortical layers of the cerebellum: the molecular layer, the purkinje cell layer, and the granule cell layer. The molecular layer contains basket cells, stellate cells and the purkinje cell and Golgi cell dendrites. The purkinje cell layer contains purkinje cell bodies and Bergmann glia. The granule cell layer contains granule cells, mossy fibers, and Golgi cell bodies. <ref>Danbolt, N. C., & Zhou, Y. (n.d.). The Cerebellar Cortex. Retrieved October 23, 2017, from http://neurotransporter.org/Cerebellum.html</ref>

===Purkinje/Pyramidal Cells===
Discovered by Jan Evangelista Purkinje in 1837, purkinje cells are inhibitory neurons found in the outside layer of the cerebellum. They receive signals from the granule cell parallel fibers and the superior olive and send inhibitory signals to the deep nuclei in the white matter region via GABA signaling. Purkinje cells have a large branching network of dendrites which allows them to be identified by their morphology.

===Granule Cells===
Named for their small cell body, cerebellar granule cells of were discovered by Camillo Golgi and Ramon y Cajal in 1899. Cerebellar granule cells are the most numerous cell type in the human brain. They receive signals from mossy fibers of the pons and synapse on the fast network of dendrites of the pyramidal cells. Cerebellar granule cells are glutamatergic and the only excitatory neurons found in the cerebellum.
<ref>D’Angelo, E. (2013). Cerebellar Granule Cell. Handbook of the Cerebellum and Cerebellar Disorders, 3, 767-791. doi: 10.1007/978-94-007-1333-8_31</ref>

===Deep Nuclei===
There are four different deep nuclei of the cerebellum: the dentate, interpositus, fastigial, and vestibular nuclei. The dentate nucleus receives signals from the lateral purkinje cells, the interpositus nucleus receives signals from the intermediate purkinje cells, the fastigial nucleus receives signals from the medial purkinje cells, and the vestibular nucleus receives signals from the flocculonodular purkinje cells. The deep nuclei integrate the inhibitory signals from the purkinje cells and the excitatory signals from the mossy and climbing fibers to determine their output signals. <ref>Harting, J. K. (1997). Deep Nuclei. Retrieved October 23, 2017, from http://www.neuroanatomy.wisc.edu/cere/text/P5/intro.htm</ref> The dentate nucleus in particular is thought to be implicated in higher level cognitive processing. It is enlarged in primates and humans and not observed in non-mammalian species.<ref name="PMID25336734"><pubmed>25336734</pubmed></ref>

===Cerebellar Nuclei===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Cerebellar Nuclei'''</center>
| width="600" |<center>'''Description''' </center>

|-
| width="40" |'''Fastigial Nucleus'''
| width="65" | Most medially located of the cerebellar nuclei. Receives input from the vermis and cerebellar afferents that carry vestibular, proximal somatosensory, auditory and visual information.

|-bgcolor="F5FAFF"
| width="40" |'''Interposed Nuclei'''
| width="65" |Consists of emboliform nucleus and globose nucleus. Interposed nuclei are situated laterally with respect to the fastigial nucleus. Receives input from intermediate zone and cerebellar afferents that carry spinal, proximal somatosensory, auditory and visual information.

|-
| width="40" |'''Dentate Nucleus'''
| width="65" |Largest of the cerebellar nuclei. Lateral to interposed nuclei. Receives input from lateral hemisphere and cerebellar afferents that carry information from cerebral cortex.

|-bgcolor="F5FAFF"
| width="40" |'''Vestibular Nuclei'''
| width="65" |Located outside cerebellum in the medulla. Considered to be cerebellar nuclei as their connectivity patterns are identical to those of cerebellar nuclei. Receive input from flocculonodular lobe and from the vestibular labyrinth.
|}

<ref>Knierim, J. (n.d.). Chapter 5: Cerebellum. Retrieved 10 3, 2017, from Neuroscience: http://neuroscience.uth.tmc.edu/s3/chapter05.html</ref>.

===Bergmann Glia===
Glial cells of the cerebellum were described by Ramon y Cajal in 1911. He divided them into 3 main categories: the glia of the white matter, the astrocytes of the granule cell layer, and the Bergmann glia of the Purkinje cell layer. Also known as Goligi epithelial cells, Bergmann glia are unipolar astrocytes that have cell bodies located in the Purkinje cell layer and long processes projecting into the molecular layer. The Bergmann glia's processes interact with the dendrites of Purkinje cells at synapses with parallel and climbing fibers. Bergmann first characterized the long processes of cells he saw in the cerebellum of cats, dogs, and humans in 1857. Ramon y Cajal later described these cells as "epithelial cells with Bergmann fibers," giving the glia their name. <ref><pubmed>12418089</pubmed></ref>

==Early Brain Vesicles==

===Primary Brain Vesicles===
[[File:Primary Brain.png]]

(Week 4) 3 primary brain vesicles are formed; forebrain (prosencephalon) midbrain (mesencephalon), and hindbrain (rhombencephalon) <ref><pubmed>22237006</pubmed></ref>

===Secondary===
[[File:Secondary brain vesicle.jpeg|700px]]

(Week 5) 3 primary vesicles develop into 5 secondary vesicles <ref><pubmed>19335795</pubmed></ref>;

*Prosencephalon develops into telencephalon (which includes the endbrain and cerebral hemispheres) and diencephalon (located between the brain and forms an optic outgrowth)

*Mesencephalon does not further develop into a secondary brain vesicle

*Rhombencephalon develops into the metencephalon (behind the brain), and myelencephalon (contains medulla)

==Metencephalon==
The metencephalon refers to the embryonic neural structure that eventually gives rise dorsally, to the cerebellum and ventrally, to the pons. The metencephalon is the anterior part of the rhombencephalon (hindbrain) and differentiates from the posterior part of the rhombencephalon (myencephalon) at week 5 of development.

The dorsal surface is characterised by its highly folded folia separated by grooves termed sulci. The median area is referred to as the vermis, which eventually becomes the most superior aspect of the cerebellum. <ref>Gerardo De Iuliis PhD, Dino Pulerà MScBMC, CMI, in The Dissection of Vertebrates (Second Edition), 2011</ref> The first structure that belies the future cerebellum are the rhombic lips that appear on the metencephalon of a 5-6 week old embryo. The rhombic lips are aptly rhombus-shaped and denote the perimeter between the roof plate and the main body of the rhombencephalon. The anterior pair of lips mark the site at which the cerebellum will develop. <ref>Bruce M. Carlson MD, PhD, in Human Embryology and Developmental Biology (Fifth Edition), 2014</ref>

=Cerebellum Developmental Weeks=

===First Trimester===
{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Week 3'''</center>
| width="65" |<center> ''Neurulation'': Notochord and somites are formed under the ectoderm. The ectoderm then forms the neural plate which then forms the neural tube and then the brain and spinal chord. </center>
| width="65" | [[File:Stage9 dorsal.jpg|200px|thumb|Early stage of neurulation]] [[File:Stage10 bf5.jpg|200px|thumb|Late stages of neurulation]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Week 4'''</center>
| width="65" |<center> Prosencephalon, mesencephalon and rhombencephalon is developed.</center>
| width="65" | [[File:Human Stage13 sagittal upper half01.jpg|200px|thumb| Sagittal view of superior end of embryo <ref> Hill, M.A. 2017 Embryology Human Stage13 sagittal upper half01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage13_sagittal_upper_half01.jpg</ref>]]

|-
| width="40" |<center>'''Week 5'''</center>
| width="65" |<center> Prosencephalon develops into telencephalon and diencephalon. The rhombencephalon differentiates into metencephalon and myelencephalon. The metencephalon will later develop the pons and cerebellum. </center>
| width="65" |<center> [[File:Human Stage14 neural01.jpg|200px|thumb|Lateral view of embryo central nervous system at 5 weeks <ref>M.A. 2017 Embryology Human Stage14 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage14_neural01.jpg</ref>]] </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''week 6'''</center>
| width="65" |<center> A pair of thickenings on the lateral side of the alar plate is formed. This is called the rhombic lip. </center>
| width="65" |<center> </center>

|-
| width="40" |<center>'''Weeks 7-9'''</center>
| width="65" |<center> The rhombic lip is fused medially to the midbrain. The primitive choroid plexus is fused with the cerebellar hemisphere to form the centrally located eosinophilic matrix. During this process, the inferior olive develops into a thick medulla forming a 'bulbo-pontine extension' <ref><pubmed>21380713</pubmed></ref>. Development of cerebellum cell layer (future Purkinje cells) and choroid plexuses of the fourth and lateral ventricles <ref><pubmed> 2252222</pubmed></ref>. </center>
| width="65" |<center> [[File:Human Stage21 neural01.jpg|200px|thumb|Left lateral view of embryonic CNS<ref>Hill, M.A. 2017 Embryology Human Stage21 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural01.jpg</ref>]] [[File:Human Stage21 neural02.jpg|200px|thumb|Left medial view of lateral embryonic CNS <ref>Hill, M.A. 2017 Embryology Human Stage21 neural02.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural02.jpg</ref>]] </center>
|}

===Second Trimester===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''weeks 11-12'''</center>
| width="65" |<center> Cerebellar hemisphere grows in size and thickness. Laminar configuration becomes present and vermis fissures start to develop. Mechanical stress such as shear and rotation can be detected by the cerebellum, causing several deep fissures to be developed <ref name="PMID21380713"><pubmed>21380713</pubmed></ref> </center>

|-
| width="40" |<center>'''Weeks 15-16'''</center>
| width="65" |<center> Nodule and flocculus is developed. Several deep fissures are formed in the vermis which has increased in thickness similar to the hemispheres <ref name="PMID21380713"/>. </center>
|}

==Neural Development==

[[File:2 day old embryo diagram.jpeg|200px|thumb|Diagram of a 2 Day Old
Embryo Illustrating the Beginnings of Neural Development <ref>Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Neural Development.</ref>]]

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the neural groove fusing to form the neural tube, which then folds to form the cranial and caudal region of the embryo, and ultimately form the cerebellum <ref>https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'</ref> . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

==Cerebellum Development==

[[File:Neural Circuit in the Cerebellum.jpg|thumb|'''Figure 5:''' Cerebellar neuronal circuits (A): Representation of zebrafish cerebellar neurons (B): Sagittal section of the adult zebrafish cerebellum (C): Zebrafish cerebellar structure schematic representation <ref><pubmed>21309081</pubmed></ref>]]
[[File:Screen Shot 2017-10-05 at 3.29.59 pm.png|thumb|'''Figure 6:''' Cerebellum cell development: A 7 day old rat cerebellum that has been sectioned to show the 3 layers of cells - external granule layer, purkinje cells and internal granular layer (a). Showing granule cell precursors proliferating to differentiate into granule neurons (b). Cell organisation (c) <ref><pubmed>4061865</pubmed></ref>]]

===Overview of Development===
As the neural tube folds, the anterior portion develops the three brain vesicles:
*Prosencephalon
*Mesencephalon
*Rhombencephalon
The rhombencephalon then further divides into the mesencephalic and myelincephalic vesicles on embryonic day 9. The neural tube failure to close then creates a gap along the dorsal sides and this produces a mouth-like structure as the tube bends to establish the pontine flexure. The pontine flexure further deepens bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brain stem) fold underneath developing the cerebellum plate <ref><pubmed>7605067</pubmed></ref>

The cerebellar territory is defined by the expression of Hoxa2 genes (from posterior) and Otx2 (from anterior) genes and these genes are controlled by proteins Wnt and fibroblast growth factor families which regulate the expression of these genes in order to establish the cerebellar territory <ref><pubmed>3213765</pubmed></ref>. Further development of the cerebellum begins between days 40 and 45 and it arises mostly from the metencephalon however the rhombic lips also contributes. The roof plate which is derived from the dorsal part of the alar plate thickens during development to become the cerebellum. The regulation of patterning involved when the primary fissure deepens by the end of the third month and thus divides the vermis, shows to be particularly important for development. The two lateral bulges are separated into the cranial anterior lob and caudal middle lobe. As the lobes divide further into lobules, fissures are formed and this continues throughout embryonic, fetal and postnatal life, thus increasing the surface area of the cerebellar cortex. The most primitive part of the cerebellum to form is the flocculonodular lobe, which is derived from separation of the first transverse fissure and this functions to keep connections with the vestibular system and it is also concerned with subconsciously controlling equilibrium. The flocculonodular lobe is separated from another crucial part of the cerebellum, corpus cerebelli, by the posterolateral fissure.

===Overview of Cerebellar Cell Development===
The cerebellum is connected to the brain stem via three pairs of peduncles and this allows the afferent and efferent pathways to enter and exit the cerebellum. Cerebellum afferent fibers can be grouped into two major types: mossy fibers and climbing fibres. Mossy fibres contribute to most of the afferent fibres in the cerebellum and they communicate with the cerebellar nuclei neurons and with Purkinje cells through granule cells embryonically, however postnatally they displace from Purkinje cells and synapse with their adult targets, the granule cell dendrites. Whilst mossy fibres originate from numerous sites in the nervous system, climbing fibers originate exclusively from the inferior olivary nucleus. Climbing fibers directly synapse with the cerebellar nuclei and Purkinje cells, relaying information to the cerebellum from several regions. The direction of these afferent fibres to their target neurons early in development are controlled by genes and molecules <ref name="PMID4552263"><pubmed>4552263</pubmed></ref>.

The cerebellum has a very basic structure consisting 2 principal classes of neurons and 3 layers, layers show in Figure 5.
*Molecular Layer: consists of excitatory granular cell axons, purkinje cell dendritic fibres. stellate and basket cells.
*Purkinje Cell Layer: consists of a single layer of inhibitory Purkinje cells.
*Granular Cell Layer: Dense layer of excitatory granule cells, golgi cells and unipolar brush cells.

The granule cells receive inputs from outside the cerebellum and project these inputs to purkinje cells where the majority of these inputs are further projected to a variety of cerebellar nuclei in the white matter <ref name="PMID25336734"/>. Within the layers there are some other main neuronal cell types, the stellate and basket cells are located in the molecular layer, whilst granule, golgi and unipolar brush cells are located in the granular layer <ref name="PMID4552263"/>. Among these principal neurons, there is a diverse set of interneurons which are responsible for coordinating the output of the Purkinje cells to the cerebellar nuclei.

The nuclei from the cerebellum are formed by a complex process of neurogenesis and neuronal migration. The dorsomedial ventricular zone of the fourth ventricle gives rise to the principal neuronal output, the Purkinje cell and other neurons within the cerebellum The secondary germinal zone, coming from the adjacent rhombic lip generates the cerebellar granule cells as well as a subpopulation of neurons of cerebellar nuclei and several precerebellar nuclei <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H., 2014. Larsen's Human Embryology E-Book. Elsevier Health Sciences.</ref>.
Granule cells function in coordinating afferent input to and motor output from the cerebellum through excitatory connections with the Purkinje cell <ref name="PMID3213765"><pubmed>3213765</pubmed></ref>. There are two types of grey matter in the cerebellum, the deep cerebellar nuclei and an external cerebellar cortex. There are 4 deep nuclei formed and the output of the cerebellar cortex are relayed through these nuclei, the ventricular layer produces 4 types of neurons that migrate to the cortex.
Proper cerebellum function requires well-organised neuronal connections and the integration of afferent and efferent fibres throughout the cerebellar circuit <ref name="PMID4552263"/>. The cerebellum functions in sensorimotor, balance control and vestibular ocular reflex, however recent studies have come out and shown that the cerebellum has a wide range of cognitive functions which include speech, memory and cognitive functions.<ref name="PMID3213765"/>

==Cellular Migration==

===Granule Cells===
Granule cells migrate tangentially from the [https://en.wikipedia.org/wiki/Rhombic_lip rhombic lip] to form the transient structure, the external germinal layer (EGL). The EGL consists of an outer and inner layer that is sandwiched between the [https://en.wikipedia.org/wiki/Pia_mater pia mater] and the purkinje cell layer. During this tangential migration, granule cells extend two horizontal processes. Granule cells move from the outer layer of the EGL to differentiate in the inner layer of the EGL. Differentiated cells continue to move radially to the granule cell layer on the inner surface of the purkinje cell layer.<ref name="PMID25336734"/> During radial migration, granule cells extend vertical processes and move through the purkinje cell layer on the radial processes of Bergmann glia.<ref name="PMID16806506"><pubmed>16806506</pubmed></ref>

===Purkinje Cells===
Purkinje cells originate from the ventricular neuroepithelium and migrate radially towards the pial surface. Many studies have shown that purkinje cells use radial glia processes as a scaffold in this migration. The movement results in a 3 to 4 cell thick layer of purkinje cells beneath the EGL. This layer becomes 1 cell thick 1 week after birth.<ref>Sotelo, C., & Rossi, F. (2013). Purkinje Cell Migration and Differentiation. Handbook of the Cerebellum and Cerebellar Disorders, 2, 147-178. doi:10.1007/978-94-007-1333-8_9</ref>

[[File:Granule Cell and Purkinje Cell Migration.png|500px]]

'''Figure 7''': Granule cell (yellow) and purkinje cell (green) migration timetable in mouse cerebellum. Top shows sagittal sections of entire cerebellum. Bottom shows movement of individual cells at interface of EGL and purkinje cell layer.<ref><pubmed>26475605</pubmed></ref>

==Cell Signalling in Cerebellar Development==
[[File:Cell signalling in cerebellum development.jpg|500px|thumb|'''Figure 8''': SHH (green) acts on EGL to stimulate proliferation, on Bergmann glia (B) to induce differentiation, and has an unknown function on purkinje cells (P). Laminin and heparan sulfate have a synergistic effect on SHH and fibronectin and vitronectin have an inhibitory effect on SHH.<ref><Pubmed>22291620</Pubmed></ref>]]
===Proliferation in the EGL===
Many different cell signalling pathways are involved with cell migration, proliferation, and differentiation in the cerebellum. [https://en.wikipedia.org/wiki/Sonic_hedgehog '''Sonic hedgehog'''] (SHH) is particularly important in the proliferation of granule cells in the external germinal layer. The '''external germinal layer''' (EGL) is the area of transit amplification of granule cell precursors. This layer is transient and lies on the external surface of the cerebellum until the cells differentiate and migrate radially to their final destination in the internal granule cell layer. SHH is secreted by the purkinje cells and acts locally, causing the granule cell precursors to undergo mitosis and Bergmann glia to differentiate. The autocrine function of SHH on the purkinje cells is unknown. <ref><pubmed>3263706</pubmed></ref> Proliferating cells in the EGL must also be positive for '''Atoh1''', a transcription factor that represses differentiation and promotes division via SHH signalling. In a similar manner to SHH and Atoh1, the pia mater secretes '''Sdf1''' which interacts with the receptor '''Cxcr4''' to maintain proliferation in the EGL. [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch2 signalling] and its stimulation of Atoh1 and repression of Bone Morphogenetic Protein (BMP).
===Exit from the EGL===
BMPs are involved in arresting granule cell proliferation in the EGL and stimulating differentiation.<ref name="PMID3051031"><pubmed>3051031</pubmed></ref> Cells exit proliferation and move to the inner EGL where they differentiate upon expression of '''Neurod1''' and interaction with the extracellular matrix components of the inner EGL, '''vitronectin''', '''F3''', and '''contactin'''.<ref name="PMID25336734"/> Granule cell migration is stimulated by '''D-serine''' secreted by the Bergmann glia. This can be inhibited by '''DAAO''' or '''SR'''.<ref name="PMID16806506"/>

[[File:Reelin signalling.jpg|300px|thumb|'''Figure 9''': Reelin is a large signalling molecule that initiates a signal transduction pathway to induce formation of a monolayer of purkinje cells and detach purkinje cells from radial glia.<ref><Pubmed>1800349</Pubmed></ref>]]
===FGF and the Isthmus===
[https://en.wikipedia.org/wiki/Fibroblast_growth_factor '''Fibroblast Growth Factor'''] (FGF) plays a role in allocating the isthmus area of the cerebellum. FGF8 is found in high concentrations in the rostral region of [https://en.wikipedia.org/wiki/Rhombomere rhombomere] 1 and decreased concentrations near the caudal region of rhombomere 1. It is necessary for the formation of the vermis of the cerebellum but the cerebellar hemispheres form independently of FGF8.<ref name="PMID25336734"/>
===Reelin and purkinje cells===
[https://en.wikipedia.org/wiki/Reelin '''Reelin'''] is an important signalling molecule that plays a role in many different in the developing brain. Reelin is a glycoprotein secreted by cells in the EGL and rhombic lip and affects purkinje cells through a signal transduction pathway involving receptors '''VLDLR''' and '''ApoER2''', adaptor protein '''Dab1''', and many other further downstream intracellular signalling molecules. Reelin has shown to play a role in formation of the monolayer of purkinje cells and detachment of purkinje cells from radial glia. It may also affect other cell morphology and migration in the cerebellum.<ref>Hevner R. F. (2008) Reelin and the Cerebellum. In: Fatemi S. H. (eds) Reelin Glycoprotein. Springer, New York, NY</ref>
===Transcription factors===
The region of rhombomere 1, a segment of the metencephalon that forms the cerebellum, is bound by the expression of the transcription factors [https://en.wikipedia.org/wiki/Hox_gene '''Hoxa2'''] and '''Otx2'''. Otx2 is expressed in the midbrain and the lack of Otx2 marks the rostral border of the cerebellar primordium. Hoxa2 is expressed in the hindbrain region and lack of Hoxa2 marks the caudal border of the cerebellar primordium.<ref name="PMID3051031"/>

==Key Historical Discoveries==
[[File:Screen Shot 2017-10-16 at 3.01.32 pm.png|200px|thumb|Figure 10: Drawing of Purkinje cells (A) and granule cells (B) from pigeon cerebellum. Drawn by Santiago Ramón y Cajal, 1899. <ref><pubmed>4308982</pubmed></ref>]]
Human interest in the cerebellum has persisted since even the early 1500's, where Galen, Vesalius and Varolio gave the first few attempts to fully describe the macroscopic anatomy of the cerebellum. However, it was not until the late 1700's that advances were made to gain experimental evidence for the function of the cerebellum. Luigi Rolando identified a specifically motor impact after cerebellar lesions developed, as opposed to an intellectual or sensory effect. This led to the conclusion that the cerebellum incited and managed movement. Pierre Flourens and Luigi Luciani were able to use this albeit crude experimentation to further define that the cerebellum coordinated movement instead of creating it, and also to differentiate between the short-term and long-term effects of cerebellar lesions, respectively. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ernesto Lugaro first defined "plasticity" as we know it in neuroscience, and also discovered the specific cells in the cerebellum that are named after him. He also furthered research into the functions of glia and defined "nervous conduction and transmission" in its current meaning. <ref name=”12481483”><pubmed>12481483</pubmed></ref>Joseph Babinski and Gordon Holmes further defined the exact nature of the effect of cerebellar lesions on motor control, and found loss of coordination in antagonistic muscles and also basic loss of muscle control. It was also found that the side of the cerebellum the lesion developed on, affected the same side of the body. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ramon y Cajal made an especially important contribution to understanding the cerebellum. He refuted Camillo Golgi's previous assertion that axons and dendrites would fuse, and also delineated the differing types of cells, most importantly of which were the mossy and climbing fibers of the cerebellum. However, this contribution could not be fully utilised until further technology was developed.

Olof Larsell is credited for developing a standard nomenclature for cerebellar anatomy that eventually spread world-wide, and for conducting a series of studies that illuminated our understanding of the rhombencephalon. <ref>"In Memoriam: Olof Larsell, 1886-1964." Journal of comparative neurology 123:1-4 (1964).</ref>
With the advent of electron microscopy, John Eccles and Janos Szentágothai in the 1960s managed to piece together the first complete map of the functional anatomy of the cerebellum and define the excitory and inhibitory nature of each cell type provided by Cajal. Further discoveries into the relationships between cell synapses, cell natures, and the minutiae of their structures by Jan Voogd, Olov Oscarsson and David Armstrong around the 1970's defined the organisation of Purkinje cells into "a series of longitudinal parasagittal bands", the specificity of which explains the solely Purkinje-axon-output of the cerebellar cortex. <ref><pubmed>19272426</pubmed></ref> The current focus in research now leans towards connecting cerebellar function with learning, emotion and perception of time.

=Animal Models=
The mouse model is a primary model organism in the study of cerebellum development, but organisms such as Drosophila (fruit fly), C. elegans (roundworm), Saccharomyces cerevisiae (Baker's yeast), cats, dogs, and cattle are also used in some types of diseases.<ref><pubmed>19669387</pubmed></ref> Looking at a variety of different of organisms' cerebellar development can elucidate the evolution of the cerebellum and further understanding of cerebellar constituents.<ref name="PMID25336734"/>

==Isthmic Organiser==
[[File:Isthmic Organiser.png|thumb|'''Figure 11:''' Isthmic Organiser <ref><pubmed>3870571</pubmed></ref>]]
Throughout history there have been many investigations on the cerebellum and how it has developed through research involving chicken embryos and mice. As previously mentioned the neural plate closes to form the neural tubes which have anterior-posterior (AP) and dorsal-ventral (DV) axes. Earlier experiments involving chick-quail chimera suggested that the cerebellum was derived from both midbrain and hindbrain. However, through successive gene expression and fate mapping studies, it was discovered that the anterior-most rhombomere of the hindbrain is where the cerebellum is formed from <ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>. Once the axes are formed the isthmic organiser (IsO) is formed which plays a vital role in establishing the anterior limit of the cerebellar territory. The IsO in other words is the mid-hindbrain boundary <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. However, the IsO does not position itself without the help of transcription factors. Studies of mouse and chicken embryos have shown that two homeo domain-containing transcription factors Otx2 and Gbx2 have an important role in positioning the isthmic organiser <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. Surgical movement of the isthmic tissue to more anterior or posterior regions of the neural tube of 10-somite stage chick embryos led to ectopic midbrain and cerebellar structures<ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>, indicating that where the IsO is placed is an important factor in establishing where the cerebellum positions.
[[File:Zebrafish.jpg|210px|thumb|right|Schematic of the cerebellar circuitry in zebrafish. PN: Purkinje neuron; E: Eurydendroid cell; G: Granule cell; S: Stellate cell. <ref name=”PMIDPMC4584246”><pubmed>PMC4584246</pubmed></ref>]]
==Cell Structures==
The cellular structures in the cerebellum (including Purkinje cells and granule cells) have been investigated in various animal models. One animal model is the zebra fish which is a bony fish (teleosts). Like mammals, the zebrafish cerebellum contains several types of neurons which function as either excitatory or inhibitory neurons <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. Glutamate is utilised by excitatory neurons as their major neurotransmitter. Excitatory neurons include granule cells, unipolar brush cells and eurydendroid cells. The eurydendoid cells are predicted to be correspondingto the deep cerebellar neurons in mammals <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. The inhibitory neurons use y-aminobutric acid (GABA) and/or glycine (also known as GABAergic neurons) for neurotransmission. Purkinje cells, Golgi and stellate cells are inhibitory neurons. However, a difference between mammal and teleosts is the lack of basket cells. Basket cells are GABAergic neurons that contribute project their axons to the Purkinje cells <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. This is important, because as earlier highlighted Purkinje cells (inhibitory neurons) and granule cells (excitatory cells) contribute to the three cortical layers of the cerebellum. This model is important for understanding what structures contribute to the neurotransmission process in the cerebellum.

=Abnormalities=
Abnormalities found within the posterior fossa of the cranium may affect the functioning and development of the cerebellum. The abnormalities affecting the cerebellum include Dandy-Walker-Malformation, Joubert Syndrome, Tecto-Cerebllar Dysraphism and Rhombencephalosynapsis (RS) which will be explained in the table below.

{| border="0"
|-bgcolor="CEDFF2"
| <center>'''Abnormality'''</center>
| <center>'''Description''' </center>
| <center>'''Brain Imaging'''</center>

|-
| <center>'''Dandy-Walker Malformation'''</center>
| Dandy-Walker-Malformation (DWM) includes the incomplete development of the cerebellar vermis with cystic dilatation of the 4th ventricle and enlargement of the posterior fossa <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The cerebellar vermis (found at the medial, cortico-nuclear zone of the cerebellum<ref name=”PMIDPMC3179064”><pubmed> PMC3179064</pubmed></ref>) may either be elevated or rotated upwards <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The communication of the 4th ventricle with the midline posterior fossa cyst can be seen on MRI scans of DWM <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. Other structures that can be identified on MRI scans include upward displacement of the tentorium and anterolateral shift of cerebellar hemispheres <ref name=”PMID21093738”><pubmed> 21093738</pubmed></ref>. The causes of DWM are still being researched and hence there has not been any clear causes. However, some causes include maternal diabetes, chromosomal defects that affect foetal brain development, infections in the mother that pass to the developing foetus and exposure of the unborn baby to certain toxins.<ref name="Pediatric Dandy-Walker Malformation. (2017). Retrieved October 23, 2017, from https://childrensnational.org/choose-childrens/conditions-and-treatments/fetal-carepregnancy/dandy-walker-malformation">Pediatric Dandy-Walker Malformation. (2017). Retrieved October 23, 2017, from https://childrensnational.org/choose-childrens/conditions-and-treatments/fetal-carepregnancy/dandy-walker-malformation</ref> Symptoms of DWM include motor and speaking development delays, poor muscle coordination, vision and hearing impairment.<ref name="Pediatric Dandy-Walker Malformation. (2017). Retrieved October 23, 2017, from https://childrensnational.org/choose-childrens/conditions-and-treatments/fetal-carepregnancy/dandy-walker-malformation"/>
| [[File:DandyWalkerMalformation.jpeg|250px|thumb|Brain MRIs. Brain imaging of patients with Dandy-Walker malformation (CCM067, CCM095) and patients with normal cerebellum and posterior fossa (CCM001). A: sagittal midline T1-weighted images. B: axial T2-weighted images. <ref name=”PMID PMC3667004”><pubmed> PMC3667004</pubmed></ref>]]

|-bgcolor="F5FAFF"
| <center>'''Joubert Syndrome'''</center>
| Joubert syndrome (JS) is described as a rare inherited genetic disorder characterised by lack of muscle coordination, intellectual disability, respiratory disturbances and abnormal eye movement <ref name=”PMIDPMC2913941”><pubmed>PMC2913941</pubmed></ref>. On neuroimaging, the cerebellar vermis is identified to have gone through hypoplasia (underdevelopment) or dysplasia (abnormal development) <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. It is also described as the "molar tooth sign" on brain imaging, which the "molar tooth" shaped is caused by the defects in the midbrain-hindbrain development. JS is inherited as mutations in any of many genes, however, how mutations lead to JS is still being investigated. Mutations cause problems in the structure and function of cilia and hence signalling pathways may be disrupted during development <ref> Joubert syndrome. (2016). Retrieved October 22, 2017, from https://rarediseases.info.nih.gov/diseases/6802/joubert-syndrome</ref>.
| [[File:JoubertSyndrome.jpg|250px|thumb|Brain Imaging of Joubert Syndrome: Cranial MRI showing “molar tooth sign” (arrows)<ref name=”PMIDPMC3896311”><pubmed>PMC3896311</pubmed></ref>]]

|-
| <center>''' Chiari Syndrome I-III'''</center>
| Chiari Syndrome I-III is when the structures within the posterior cranial fossa protrude into the spinal canal <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref> which can affect the development and functioning of the cerebellum in the long term. Chiari Syndrome can be classified into four types. The downward shift of the cerebellar tonsils to beneath the foramen magnum is type 1 and the downward movement of the vermis, medulla oblongata and pons with the fourth ventricle is type 2 <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>. When majority of the cerebellum lies in the foramen magnum it is type 3 and when it is completely in the foramen magnum (and therefore cannot develop normally) it is type 4<ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>. As a result of genetic mutations or maternal diet lacking vitamins or nutrients, structural defects in the brain and spinal cord can occur during foetal development leading to Chiari Syndrome <ref> Chiari Malformation Fact Sheet. (2017). Retrieved October 22, 2017, from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Chiari-Malformation-Fact-Sheet</ref>
| [[File:ChiariMalformation.jpg|250px|thumb|Cerebellar tonsils herniation on magnetic resonance imaging: Chiari malformation type I<ref name=”PMIDPMC4279813”><pubmed>PMC4279813</pubmed></ref>]]

|-bgcolor="F5FAFF"
| <center>'''Rhombencephalosynapsis'''</center>
| Rhombencephalosynapsis is a rare cerebellar defect whereby there is dorsal fusion of the cerebral hemispheres, fusion of dentate nuclei and superior cerebellar peduncles as well as the agenesis of the cerebella vermis <ref name=”PMID18155944”><pubmed>18155944</pubmed></ref>. Rhombencephalosynapsis is predicted to result from disturbed cerebellar development at approximately 33–34 days of gestation <ref name=”PMID18409180”><pubmed>18409180</pubmed></ref>. The cause of rhombencephalosynapsis is thought to be a genetic defect in the isthmic organizer, resulting in abnormal dorsal patterning, causing the mentioned defects <ref name=”PMID18409180”><pubmed>18409180</pubmed></ref>. Like other mentioned abnormalities there is development delay because of the underdeveloped cerebellum. Rhombencephalosynapsis can be identified from a range of symptoms, from involuntary muscle coordination, severe cerebral palsy or mental retardation<ref name=”PMID25816977”><pubmed>25816977</pubmed></ref>.
| <center>[[File:Rhombencephalosynapsis.jpg|250px|thumb|Partial Rhombencephalosynapsis with fused upper parts of the cerebellum<ref name=”PMIDPMC3447431”><pubmed>PMC3447431</pubmed></ref>]]</center>
|}

=Current Research=
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516611/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429509/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571438/

=Future Questions=
Is the cerebellum size related to human intelligence?

Does the p53 gene function in cerebellum development? If so, does this function relate to the development of embryonic cancers? <ref name=”PMC4853753”><pubmed> 4853753</pubmed></ref>

=Terms=

* '''Basket cells'''– multipolar GABAergic interneurons. They are located on different regions of the brain and cerebellum. They function in making inhibitory synapses and control the overall potential of target cells.
* '''Bergmann Glia ''' – they are a type of radial astrocyte, cell bodies are in the Purkinje cell layer of the cerebellum.
* '''Cerebellar nuclei ''' – These cells receive inhibitory inputs from the purkinje cells, and excitatory inputs from mossy and climbing fibres.
* '''Climbing fibres ''' – provide excitatory input to the cerebellum, they have a crucial role in motor behaviors. Axons pass through the pons, then synapse with the deep cerebellar nuclei and purkinje cells.
* '''Deep nuclei cells''' – Purkinje cells project to the deep nuclei cells and these are the only form of output cell in the cerebellar cortex. They also receive excitatory inputs from the mossy and climbing fibers.
* '''Dendrites ''' – an extension of a nerve cell, impulses travel along these extensions and they synapse at another cell body.
* '''Flocculonodular lobe ''' – lobe of the cerebellum that consists of a nodule and the flocculus. It is located on the anteroinferior surface of the cerebellum.
* '''Glia cells ''' – They are nonneuronal cells and they support cells and they surround neurons and insulate them, there are many types of glia cells: oligodendrocytes, ependymal cells, astrocytes, Schwann cells etc.
* '''Granule cells ''' – are small neurons, and they are the most numerous in the brain. They are packed in a thick layer of the cerebellar cortex and emit only 4 or 5 dendrites. They receive all input from mossy fibres.
* '''Mossy fibres ''' – major input of the cerebellum, relays sensory information from the pons to the granule cells and then sent to the purkinje cells for processing.
* '''Neural tube ''' – a hollow prenatal structure that forms the brain and spinal cord. Formed by the folding and fusion of the opposite ectodermal folds.
* '''Pons ''' – a part of the brain that links the medulla oblongata and the thalamus.
* '''Purkinje cells ''' – a class of GABAnergic neurons that are located in the cortex of the cerebellum, they are large, branched cells.
* '''Stellate cells ''' – in the cerebellum, they are located in the molecular layer and they synapse onto purkinje cells.
* '''Vermis ''' – rounded and elongated section of the central part of cerebellum, lies between the two hemispheres.
* '''Vetrobrobasilar System ''' – consists of the two vertebral arteries and one basilar artery and these are located towards the back of the brain. Provide around 20% of the intracranial bloody supply.

{{Glossary}}

=References=
<references/>

File:Primary Brain.png

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Z5076158: In week 4, 3 primary brain vesicles are formed; forebrain (prosencephalon) midbrain (mesencephalon), and hindbrain (rhombencephalon). These structures then differentiate into 5 secondary brain vesicles during week 5. Drawn by Student z5076158 {{Templ...

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(A). Cell types and where they are found in the cerebellar cortical layers. (B) Shows how the different layers of the cerebellum can be easily determined. P - the Purkinje layer; G - the granular layer; M - the molecular layer; W - the white matter. <ref><pubmed>3527225</pubmed></ref>

=Copyright=
</references>
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

{{Template:Student Image}}

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(A). Cell types and where they are found in the cerebellar cortical layers. (B) Shows how the different layers of the cerebellum can be easily determined. P - the Purkinje layer; G - the granular layer; M - the molecular layer; W - the white matter. <ref><pubmed>3527225</pubmed><ref>

=Copyright=
</references>
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.

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=Cerebellum=

=Introduction=
The cerebellum is a large portion of the brain that functions in coordination, balance and control, and its development occurs both prenatally and postnatally. The cerebellum underlies the occipital and temporal lobes of the cerebral cortex and constitutes to about 10% of the brains weight however contains around 50% of the neurons.
This page will highlight the anatomy of the cerebellum, its developmental process, current research on the structure, animal models and abnormalities associated with it. The anatomy will discuss the distinguishable lobes and zones of the cerebellum. The anatomy of the cerebellum cannot be completely discussed without explaining the vasculature of the structure and hence this page will provide a brief overview of it. The development of the cerebellum discusses the neural development and where the cerebellum forms on the neural tube. The development will highlight how the circuitry of the post-natal cerebellum came to be from neurons. Hence purkinje cells, granule cells, deep nuclei cells, glia cells and cerebellar nuclei will be highlighted to discuss the developmental process. A developmental timeline of the formation of the cerebellum is also included on this page. The cerebellum is a topic of continuous research and past findings would not have been done without the use of animal models, hence current research and animal models will be discussed. The abnormalities that could happen if the cerebellum were to be affected is also highlighted.

=Basic Anatomy of the Cerebellum=

The cerebellum has 3 distinguishable lobes; flocculonodular lobe, anterior lobe and the posterior lobe. The anterior and posterior lobe can be further divided in a midline cerebellar vermis and lateral cerebellar hemispheres (Figure 1)
<ref name=”PMID9735944”><pubmed> 9735944</pubmed></ref>. In a superior cerebellar view, the cerebellum contains a vermis that runs through the middle of the organ and 2 intermediate zones located laterally from the vermis (Figure 2).

[[File:Anatomical-Lobes-of-the-Cerebellum.jpg|500px]]

'''Figure 1:''' Anatomical lobes observed in the cerebellum; anterior lobe, posterior lobe and flocculonodular lobe, which is divided by two fissures – the primary fissure and posterolateral fissure <ref>http://teachmeanatomy.info/neuro/structures/cerebellum</ref>

[[File:Cerebellum anatomical subdivisions.png|500px]]

'''Figure 2:''' Superior view of the 3 cerebellar zones. The middle is the vermis. Either side of the vermis is the intermediate zone. Lateral to the intermediate zone is the lateral hemispheres. There is no difference in gross structure between the lateral hemispheres and intermediate zones. <ref>https://commons.wikimedia.org/wiki/File:CerebellumDiv.png</ref>

[[File:Arteries of the cerebellum.jpeg|thumb|'''Figure 3:''' Diagram of the main arteries of the cerebellum <ref>http://teachmeanatomy.info/neuro/structures/cerebellum/</ref>]]

==Vasculature==
The cerebellum contains 3 bilateral paired arteries which supplies this organ with oxygenated blood. These arteries all originate from the vertebrobasilar system; Superior Cerebellar Artery (SCA), Anterior Inferior Cerebellar Artery (AICA) and the Posterior inferior cerebellar artery (PICA). The SCA and AICA are branches of the basilar artery, which wraps around the anterior aspect of the pons before reaching the cerebellum. The PICA arises from the left and right vertebral artery, which form the basilar artery <ref>https://www.ncbi.nlm.nih.gov/books/NBK11042/</ref>. The PICA and AICA combine to supply the inferior half of the cerebellum, while the SCA supplies the majority of the superior half. The PICA and SCA combine to supply the vermis<ref name=”PMID2535662”><pubmed> 2535662</pubmed></ref>. Blood is then drained by superior and inferior cerebellar veins into the superior petrosal and then straight dural venous sinuses. (Figure 3) <ref name=”PMID27766499”><pubmed> 27766499</pubmed></ref>

==Ectoderm==

There are 3 germ layers present in the early embryo; ectoderm (most distal layer), mesoderm (middle layer) and endoderm (most proximal layer). The ectoderm differentiates into the nervous system, forming the spine, peripheral nerves, cerebrum and cerebellum. It also differentiates to form tooth enamel, epidermis, and the linings of the mouth, anus, sweat glands and nostrils<ref name=”PMID14550785”><pubmed> 14550785</pubmed></ref>.

==Microanatomy==
===Cortical Layers===
There are 3 major cortical layers of the cerebellum: the molecular layer, the purkinje cell layer, and the granule cell layer. The molecular layer contains basket cells, stellate cells and the purkinje cell and Golgi cell dendrites. The purkinje cell layer contains purkinje cell bodies and Bergmann glia. The granule cell layer contains granule cells, mossy fibers, and Golgi cell bodies. <ref>http://neurotransporter.org/Cerebellum.html</ref>

===Purkinje/Pyramidal Cells===
Discovered by Jan Evangelista Purkinje in 1837, purkinje cells are inhibitory neurons found in the outside layer of the cerebellum. They receive signals from the granule cell parallel fibers and the superior olive and send inhibitory signals to the deep nuclei in the white matter region via GABA signaling. Purkinje cells have a large branching network of dendrites which allows them to be identified by their morphology.

===Granule Cells===
Named for their small cell body, cerebellar granule cells of were discovered by Camillo Golgi and Ramon y Cajal in 1899. Cerebellar granule cells are the most numerous cell type in the human brain. They receive signals from mossy fibers of the pons and synapse on the fast network of dendrites of the pyramidal cells. Cerebellar granule cells are glutamatergic and the only excitatory neurons found in the cerebellum.
<ref>https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-1333-8_31</ref>

===Deep Nuclei===
There are four different deep nuclei of the cerebellum: the dentate, interpositus, fastigial, and vestibular nuclei. The dentate nucleus receives signals from the lateral purkinje cells, the interpositus nucleus receives signals from the intermediate purkinje cells, the fastigial nucleus receives signals from the medial purkinje cells, and the vestibular nucleus receives signals from the flocculonodular purkinje cells. The deep nuclei integrate the inhibitory signals from the purkinje cells and the excitatory signals from the mossy and climbing fibers to determine their output signals. <ref>http://www.neuroanatomy.wisc.edu/cere/text/P5/intro.htm</ref> The dentate nucleus in particular is thought to be implicated in higher level cognitive processing. It is enlarged in primates and humans and not observed in non-mammalian species.<ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref>

===Bergmann Glia===
Glial cells of the cerebellum were described by Ramon y Cajal in 1911. He divided them into 3 main categories: the glia of the white matter, the astrocytes of the granule cell layer, and the Bergmann glia of the Purkinje cell layer. Also known as Goligi epithelial cells, Bergmann glia are unipolar astrocytes that have cell bodies located in the Purkinje cell layer and long processes projecting into the molecular layer. The Bergmann glia's processes interact with the dendrites of Purkinje cells at synapses with parallel and climbing fibers. Bergmann first characterized the long processes of cells he saw in the cerebellum of cats, dogs, and humans in 1857. Ramon y Cajal later described these cells as "epithelial cells with Bergmann fibers," giving the glia their name. <ref>https://link.springer.com/content/pdf/10.1046%2Fj.0022-7722.2002.00021.x.pdf</ref>

===Cerebellar Nuclei===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Cerebellar Nuclei'''</center>
| width="600" |<center>'''Description''' </center>

|-
| width="40" |<center>'''Fastigial Nucleus'''</center>
| width="65" |<center> Most medially located of the cerebellar nuclei. Receives input from the vermis and cerebellar afferents that carry vestibular, proximal somatosensory, auditory and visual information. </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Interposed Nuclei'''</center>
| width="65" |<center> Consists of emboliform nucleus and globose nucleus. Interposed nuclei are situated laterally with respect to the fastigial nucleus. Receives input from intermediate zone and cerebellar afferents that carry spinal, proximal somatosensory, auditory and visual information. </center>

|-
| width="40" |<center>'''Dentate Nucleus'''</center>
| width="65" |<center> Largest of the cerebellar nuclei. Lateral to interposed nuclei. Receives input from lateral hemisphere and cerebellar afferents that carry information from cerebral cortex. </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''Vestibular Nuclei'''</center>
| width="65" |<center> Located outside cerebellum in the medulla. Considered to be cerebellar nuclei as their connectivity patterns are identical to those of cerebellar nuclei. Receive input from flocculonodular lobe and from the vestibular labyrinth. </center>
|}

<ref>Knierim, J. (n.d.). Chapter 5: Cerebellum. Retrieved 10 3, 2017, from Neuroscience: http://neuroscience.uth.tmc.edu/s3/chapter05.html</ref>.

==Early Brain Vesicles==

===Primary Brain Vesicles===
[[File:Primary Brain Vesicles.jpeg]]

(Week 4) 3 primary brain vesicles are formed; forebrain (prosencephalon) midbrain (mesencephalon), and hindbrain (rhombencephalon) <ref>https://www.karger.com/Article/FullText/334842</ref>

===Secondary===
[[File:Secondary brain vesicle.jpeg|700px]]

(Week 5) 3 primary vesicles develop into 5 secondary vesicles <ref>http://onlinelibrary.wiley.com/doi/10.1111/j.1447-0756.2008.00964.x/full</ref>;

*Prosencephalon develops into telencephalon (which includes the endbrain and cerebral hemispheres) and diencephalon (located between the brain and forms an optic outgrowth)

*Mesencephalon does not further develop into a secondary brain vesicle

*Rhombencephalon develops into the metencephalon (behind the brain), and myelencephalon (contains medulla)

==Metencephalon==
The metencephalon refers to the embryonic neural structure that eventually gives rise dorsally, to the cerebellum and ventrally, to the pons. The metencephalon is the anterior part of the rhombencephalon (hindbrain) and differentiates from the posterior part of the rhombencephalon (myencephalon) at week 5 of development.

The dorsal surface is characterised by its highly folded folia separated by grooves termed sulci. The median area is referred to as the vermis, which eventually becomes the most superior aspect of the cerebellum. <ref>Gerardo De Iuliis PhD, Dino Pulerà MScBMC, CMI, in The Dissection of Vertebrates (Second Edition), 2011</ref> The first structure that belies the future cerebellum are the rhombic lips that appear on the metencephalon of a 5-6 week old embryo. The rhombic lips are aptly rhombus-shaped and denote the perimeter between the roof plate and the main body of the rhombencephalon. The anterior pair of lips mark the site at which the cerebellum will develop. <ref>Bruce M. Carlson MD, PhD, in Human Embryology and Developmental Biology (Fifth Edition), 2014</ref>

=Cerebellum Developmental Weeks=

===First Trimester===
{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>
| width="600" |<center>'''Images'''</center>

|-
| width="40" |<center>'''Week 3'''</center>
| width="65" |<center> ''Neurulation'': Notochord and somites are formed under the ectoderm. The ectoderm then forms the neural plate which then forms the neural tube and then the brain and spinal chord. </center>
| width="65" | [[File:Stage9 dorsal.jpg|200px|thumb|Early stage of neurulation]] [[File:Stage10 bf5.jpg|200px|thumb|Late stages of neurulation]]

|-bgcolor="F5FAFF"
| width="40" |<center>'''Week 4'''</center>
| width="65" |<center> Prosencephalon, mesencephalon and rhombencephalon is developed.</center>
| width="65" | [[File:Human Stage13 sagittal upper half01.jpg|200px|thumb| Sagittal view of superior end of embryo <ref> Hill, M.A. 2017 Embryology Human Stage13 sagittal upper half01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage13_sagittal_upper_half01.jpg</ref>]]

|-
| width="40" |<center>'''Week 5'''</center>
| width="65" |<center> Prosencephalon develops into telencephalon and diencephalon. The rhombencephalon differentiates into metencephalon and myelencephalon. The metencephalon will later develop the pons and cerebellum. </center>
| width="65" |<center> [[File:Human Stage14 neural01.jpg|200px|thumb|Lateral view of embryo central nervous system at 5 weeks <ref>M.A. 2017 Embryology Human Stage14 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage14_neural01.jpg</ref>]] </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''week 6'''</center>
| width="65" |<center> A pair of thickenings on the lateral side of the alar plate is formed. This is called the rhombic lip. </center>
| width="65" |<center> </center>

|-
| width="40" |<center>'''Weeks 7-9'''</center>
| width="65" |<center> The rhombic lip is fused medially to the midbrain. The primitive choroid plexus is fused with the cerebellar hemisphere to form the centrally located eosinophilic matrix. During this process, the inferior olive develops into a thick medulla forming a 'bulbo-pontine extension' <ref><pubmed>21380713</pubmed></ref>. Development of cerebellum cell layer (future Purkinje cells) and choroid plexuses of the fourth and lateral ventricles <ref><pubmed> 2252222</pubmed></ref>. </center>
| width="65" |<center> [[File:Human Stage21 neural01.jpg|200px|thumb|Left lateral view of embryonic CNS<ref>Hill, M.A. 2017 Embryology Human Stage21 neural01.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural01.jpg</ref>]] [[File:Human Stage21 neural02.jpg|200px|thumb|Left medial view of lateral embryonic CNS <ref>Hill, M.A. 2017 Embryology Human Stage21 neural02.jpg. Retrieved October 4, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/File:Human_Stage21_neural02.jpg</ref>]] </center>
|}

===Second Trimester===

{| border="0"
|-bgcolor="CEDFF2"
| width="300" |<center>'''Week'''</center>
| width="600" |<center>'''Development''' </center>

|-bgcolor="F5FAFF"
| width="40" |<center>'''weeks 11-12'''</center>
| width="65" |<center> Cerebellar hemisphere grows in size and thickness. Laminar configuration becomes present and vermis fissures start to develop. Mechanical stress such as shear and rotation can be detected by the cerebellum, causing several deep fissures to be developed <ref><pubmed>21380713</pubmed></ref> </center>

|-
| width="40" |<center>'''Weeks 15-16'''</center>
| width="65" |<center> Nodule and flocculus is developed. Several deep fissures are formed in the vermis which has increased in thickness similar to the hemispheres <ref><pubmed>21380713</pubmed></ref>. </center>
|}

==Neural Development==

[[File:2 day old embryo diagram.jpeg|200px|thumb|Diagram of a 2 Day Old
Embryo Illustrating the Beginnings of Neural Development <ref>Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Neural Development.</ref>]]

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the neural groove fusing to form the neural tube, which then folds to form the cranial and caudal region of the embryo, and ultimately form the cerebellum <ref>https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'</ref> . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

==Cerebellum Development==

[[File:Neural Circuit in the Cerebellum.jpg|thumb|'''Figure 4:''' Cerebellar neuronal circuits (A): Representation of zebrafish cerebellar neurons (B): Sagittal section of the adult zebrafish cerebellum (C): Zebrafish cerebellar structure schematic representation <ref><pubmed>21309081</pubmed></ref>]]
[[File:Screen Shot 2017-10-05 at 3.29.59 pm.png|thumb|'''Figure 5:''' Cerebellum cell development: A 7 day old rat cerebellum that has been sectioned to show the 3 layers of cells - external granule layer, purkinje cells and internal granular layer (a). Showing granule cell precursors proliferating to differentiate into granule neurons (b). Cell organisation (c) <ref><pubmed>4061865</pubmed></ref>]]

===Overview of Development===
As the neural tube folds, the anterior portion develops the three brain vesicles:
*Prosencephalon
*Mesencephalon
*Rhombencephalon
The rhombencephalon then further divides into the mesencephalic and myelincephalic vesicles on embryonic day 9. The neural tube failure to close then creates a gap along the dorsal sides and this produces a mouth-like structure as the tube bends to establish the pontine flexure. The pontine flexure further deepens bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brain stem) fold underneath developing the cerebellum plate <ref><pubmed>7605067</pubmed></ref>

The cerebellar territory is defined by the expression of Hoxa2 genes (from posterior) and Otx2 (from anterior) genes and these genes are controlled by proteins Wnt and fibroblast growth factor families which regulate the expression of these genes in order to establish the cerebellar territory <ref><pubmed>3213765</pubmed></ref>. Further development of the cerebellum begins between days 40 and 45 and it arises mostly from the metencephalon however the rhombic lips also contributes. The roof plate which is derived from the dorsal part of the alar plate thickens during development to become the cerebellum. The regulation of patterning involved when the primary fissure deepens by the end of the third month and thus divides the vermis, shows to be particularly important for development. The two lateral bulges are separated into the cranial anterior lob and caudal middle lobe. As the lobes divide further into lobules, fissures are formed and this continues throughout embryonic, fetal and postnatal life, thus increasing the surface area of the cerebellar cortex. The most primitive part of the cerebellum to form is the flocculonodular lobe, which is derived from separation of the first transverse fissure and this functions to keep connections with the vestibular system and it is also concerned with subconsciously controlling equilibrium. The flocculonodular lobe is separated from another crucial part of the cerebellum, corpus cerebelli, by the posterolateral fissure.

===Overview of Cerebellar Cell Development===
The cerebellum is connected to the brain stem via three pairs of peduncles and this allows the afferent and efferent pathways to enter and exit the cerebellum. Cerebellum afferent fibers can be grouped into two major types: mossy fibers and climbing fibres. Mossy fibres contribute to most of the afferent fibres in the cerebellum and they communicate with the cerebellar nuclei neurons and with Purkinje cells through granule cells embryonically, however postnatally they displace from Purkinje cells and synapse with their adult targets, the granule cell dendrites. Whilst mossy fibres originate from numerous sites in the nervous system, climbing fibers originate exclusively from the inferior olivary nucleus. Climbing fibers directly synapse with the cerebellar nuclei and Purkinje cells, relaying information to the cerebellum from several regions. The direction of these afferent fibres to their target neurons early in development are controlled by genes and molecules <ref><pubmed>4552263</pubmed></ref>.

The cerebellum has a very basic structure consisting 2 principal classes of neurons and 3 layers, layers show in Figure 4.
*Molecular Layer: consists of excitatory granular cell axons, purkinje cell dendritic fibres. stellate and basket cells.
*Purkinje Cell Layer: consists of a single layer of inhibitory Purkinje cells.
*Granular Cell Layer: Dense layer of excitatory granule cells, golgi cells and unipolar brush cells.

The granule cells receive inputs from outside the cerebellum and project these inputs to purkinje cells where the majority of these inputs are further projected to a variety of cerebellar nuclei in the white matter <ref><pubmed>25336734</pubmed></ref>. Within the layers there are some other main neuronal cell types, the stellate and basket cells are located in the molecular layer, whilst granule, golgi and unipolar brush cells are located in the granular layer <ref><pubmed>4552263</pubmed></ref>. Among these principal neurons, there is a diverse set of interneurons which are responsible for coordinating the output of the Purkinje cells to the cerebellar nuclei.

The nuclei from the cerebellum are formed by a complex process of neurogenesis and neuronal migration. The dorsomedial ventricular zone of the fourth ventricle gives rise to the principal neuronal output, the Purkinje cell and other neurons within the cerebellum The secondary germinal zone, coming from the adjacent rhombic lip generates the cerebellar granule cells as well as a subpopulation of neurons of cerebellar nuclei and several precerebellar nuclei <ref>Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H., 2014. Larsen's Human Embryology E-Book. Elsevier Health Sciences.</ref>.
Granule cells function in coordinating afferent input to and motor output from the cerebellum through excitatory connections with the Purkinje cell <ref><pubmed>3213765</pubmed></ref>. There are two types of grey matter in the cerebellum, the deep cerebellar nuclei and an external cerebellar cortex. There are 4 deep nuclei formed and the output of the cerebellar cortex are relayed through these nuclei, the ventricular layer produces 4 types of neurons that migrate to the cortex.
Proper cerebellum function requires well-organised neuronal connections and the integration of afferent and efferent fibres throughout the cerebellar circuit <ref><pubmed>4552263</pubmed></ref>. The cerebellum functions in sensorimotor, balance control and vestibular ocular reflex, however recent studies have come out and shown that the cerebellum has a wide range of cognitive functions which include speech, memory and cognitive functions <ref><pubmed>3213765</pubmed></ref>.

==Cellular Migration==

===Granule Cells===
Granule cells migrate tangentially from the rhombic lip to form the transient structure, the external germinal layer (EGL). The EGL consists of an outer and inner layer that is sandwiched between the pia mater and the purkinje cell layer. During this tangential migration, granule cells extend two horizontal processes. Granule cells move from the outer layer of the EGL to differentiate in the inner layer of the EGL. Differentiated cells continue to move radially to the granule cell layer on the inner surface of the purkinje cell layer<ref>http://dev.biologists.org/content/141/21/4031</ref> During radial migration, granule cells extend vertical processes and move through the purkinje cell layer on the radial processes of Bergmann glia.<ref>https://www.researchgate.net/publication/6977220_d-Serine_signalling_in_the_brain_friend_and_foe/figures?lo=1</ref>

===Purkinje Cells===
Purkinje cells originate from the ventricular neuroepithelium and migrate radially towards the pial surface. Many studies have shown that purkinje cells use radial glia processes as a scaffold in this migration. The movement results in a 3 to 4 cell thick layer of purkinje cells beneath the EGL. This layer becomes 1 cell thick 1 week after birth.<ref>https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-1333-8_9</ref>

[[File:Granule Cell and Purkinje Cell Migration.png]]

Figure 6: Granule cell (yellow) and purkinje cell (green) migration timetable in mouse cerebellum. Top shows sagittal sections of entire cerebellum. Bottom shows movement of individual cells at interface of EGL and purkinje cell layer.<ref><pubmed>26475605</pubmed></ref>

==Cell Signaling in Cerebellar Development==
Many different cell signaling pathways are involved with cell migration, proliferation, and differentiation in the cerebellum. Sonic hedgehog (SHH) is particularly important in the proliferation of granule cells in the external germinal layer. The external germinal layer (EGL) is the area of transit amplification of granule cell precursors. This layer is transient and lies on the external surface of the cerebellum until the cells differentiate and migrate radially to their final destination in the internal granule cell layer. SHH is secreted by the purkinje cells and acts locally, causing the granule cell precursors to undergo mitosis and Bergmann glia to differentiate. The autocrine function of SHH on the purkinje cells is unknown. <ref><pubmed>3263706</pubmed></ref> Proliferating cells in the EGL must also be positive for Atoh1, a transcription factor that represses differentiation and promotes division via SHH signaling. In a similar manner to SHH and Atoh1, the pia mater secretes Sdf1 which interacts with the receptor Cxcr4 to maintain proliferation in the EGL. Notch2 signaling and its stimulation of Atoh1 and repression of Bone Morphogenetic Protein (BMP). BMPs are involved in arresting granule cell proliferation in the EGL and stimulating differentiation.<ref><pubmed>3051031</pubmed></ref> Cells exit proliferation and move to the inner EGL where they differentiate upon expression of Neurod1 and interaction with the extracellular matrix components of the inner EGL, vitronectin, F3, and contactin. <ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref> Granule cell migration is stimulated by D-serine secreted by the Bergmann glia. This can be inhibited by DAAO or SR.<ref>Magalie Martineau, Gérard Baux, Jean-Pierre Mothet D-serine signalling in the brain: friend and foe. Trends Neurosci.: 2006, 29(8);481-91 PubMed 16806506</ref>

Fibroblast Growth Factor (FGF) plays a role in allocating the isthmus area of the cerebellum. FGF8 is found in high concentrations in the rostral region of rhombomere 1 and decreased concentrations near the caudal region of rhombomere 1. It is necessary for the formation of the vermis of the cerebellum but the cerebellar hemispheres form independently of FGF8.<ref>Thomas Butts, Mary J Green, Richard J T Wingate Development of the cerebellum: simple steps to make a 'little brain'. Development: 2014, 141(21);4031-41 PubMed 25336734</ref>

Reelin is an important signaling molecule that plays a role in many different in the developing brain. Reelin is a glycoprotein secreted by cells in the EGL and rhombic lip and affects purkinje cells through a signal transduction pathway involving receptors VLDLR and ApoER2, adaptor protein Dab1, and many other further downstream intracellular signaling molecules. Reelin has shown to play a role in formation of the monolayer of purkinje cells and detachment of purkinje cells from radial glia. It may also affect other cell morphology and migration in the cerebellum.<ref>Hevner R. F. (2008) Reelin and the Cerebellum. In: Fatemi S. H. (eds) Reelin Glycoprotein. Springer, New York, NY</ref>

The region of rhombomere 1, a segment of the metencephalon that forms the cerebellum, is bound by the expression of the transcription factors Hoxa2 and Otx2. Otx2 is expressed in the midbrain and the lack of Otx2 marks the rostral border of the cerebellar primordium. Hoxa2 is expressed in the hindbrain region and lack of Hoxa2 marks the caudal border of the cerebellar primordium.<ref><pubmed>3051031</pubmed></ref>

==Key Historical Discoveries==
Human interest in the cerebellum has persisted since even the early 1500's, where Galen, Vesalius and Varolio gave the first few attempts to fully describe the macroscopic anatomy of the cerebellum. However, it was not until the late 1700's that advances were made to gain experimental evidence for the function of the cerebellum. Luigi Rolando identified a specifically motor impact after cerebellar lesions developed, as opposed to an intellectual or sensory effect. This led to the conclusion that the cerebellum incited and managed movement. Pierre Flourens and Luigi Luciani were able to use this albeit crude experimentation to further define that the cerebellum coordinated movement instead of creating it, and also to differentiate between the short-term and long-term effects of cerebellar lesions, respectively. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ernesto Lugaro first defined "plasticity" as we know it in neuroscience, and also discovered the specific cells in the cerebellum that are named after him. He also furthered research into the functions of glia and defined "nervous conduction and transmission" in its current meaning. <ref name=”12481483”><pubmed>12481483</pubmed></ref>Joseph Babinski and Gordon Holmes further defined the exact nature of the effect of cerebellar lesions on motor control, and found loss of coordination in antagonistic muscles and also basic loss of muscle control. It was also found that the side of the cerebellum the lesion developed on, affected the same side of the body. <ref name=”PMID19272426”><pubmed>19272426</pubmed></ref>

Ramon y Cajal made an especially important contribution to understanding the cerebellum. He refuted Camillo Golgi's previous assertion that axons and dendrites would fuse, and also delineated the differing types of cells, most importantly of which were the mossy and climbing fibers of the cerebellum. However, this contribution could not be fully utilised until further technology was developed.

Olof Larsell is credited for developing a standard nomenclature for cerebellar anatomy that eventually spread world-wide, and for conducting a series of studies that illuminated our understanding of the rhombencephalon. <ref>"In Memoriam: Olof Larsell, 1886-1964." Journal of comparative neurology 123:1-4 (1964).</ref>
With the advent of electron microscopy, John Eccles and Janos Szentágothai in the 1960s managed to piece together the first complete map of the functional anatomy of the cerebellum and define the excitory and inhibitory nature of each cell type provided by Cajal. Further discoveries into the relationships between cell synapses, cell natures, and the minutiae of their structures by Jan Voogd, Olov Oscarsson and David Armstrong around the 1970's defined the organisation of Purkinje cells into "a series of longitudinal parasagittal bands", the specificity of which explains the solely Purkinje-axon-output of the cerebellar cortex. <ref>https://www.ncbi.nlm.nih.gov/pubmed/19272426</ref> The current focus in research now leans towards connecting cerebellar function with learning, emotion and perception of time.

=Animal Models=
The mouse model is a primary model organism in the study of cerebellum development, but organisms such as Drosophila (fruit fly), C. elegans (roundworm), Saccharomyces cerevisiae (Baker's yeast), cats, dogs, and cattle are also used in some types of diseases.<ref><pubmed>19669387</pubmed></ref> Looking at a variety of different of organisms' cerebellar development can elucidate the evolution of the cerebellum and further understanding of cerebellar constituents.<ref><pubmed>25336734</pubmed></ref>

==Isthmic Organiser==
Throughout history there have been many investigations on the cerebellum and how it has developed through research involving chicken embryos and mice. As previously mentioned the neural plate closes to form the neural tubes which have anterior-posterior (AP) and dorsal-ventral (DV) axes. Earlier experiments involving chick-quail chimera suggested that the cerebellum was derived from both midbrain and hindbrain. However, through successive gene expression and fate mapping studies, it was discovered that the anterior-most rhombomere of the hindbrain is where the cerebellum is formed from <ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>. Once the axes are formed the isthmic organiser (IsO) is formed which plays a vital role in establishing the anterior limit of the cerebellar territory. The IsO in other words is the mid-hindbrain boundary <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. However, the IsO does not position itself without the help of transcription factors. Studies of mouse and chicken embryos have shown that two homeo domain-containing transcription factors Otx2 and Gbx2 have an important role in positioning the isthmic organiser <ref name=”PMID21309081”><pubmed>21309081</pubmed></ref>. Surgical movement of the isthmic tissue to more anterior or posterior regions of the neural tube of 10-somite stage chick embryos led to ectopic midbrain and cerebellar structures<ref name=”PMID14567957”><pubmed> 14567957</pubmed></ref>, indicating that where the IsO is placed is an important factor in establishing where the cerebellum positions.

=Abnormalities=
Abnormalities found within the posterior fossa of the cranium may affect the functioning and development of the cerebellum. The abnormalities affecting the cerebellum include Dandy-Walker-Malformation, Joubert Syndrome, Tecto-Cerebllar Dysraphism and Rhombencephalosynapsis (RS).
==Dandy-Walker Malformation==
Dandy-Walker-Malformation (DWM) includes the incomplete development of the cerebellar vermis with cystic dilatation of the 4th ventricle and enlargement of the posterior fossa <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The cerebellar vermis (found at the medial, cortico-nuclear zone of the cerebellum<ref name=”PMIDPMC3179064”><pubmed> PMC3179064</pubmed></ref>) may either be elevated or rotated upwards <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. The communication of the 4th ventricle with the midline posterior fossa cyst can be seen on MRI scans of DWM <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. Other structures that can be identified on MRI scans include upward displacement of the tentorium and anterolateral shift of cerebellar hemispheres <ref name=”PMID21093738”><pubmed> 21093738</pubmed></ref>.

[[File:DandyWalkerMalformation.jpeg|435px]]

Brain MRIs. Brain imaging of patients with Dandy-Walker malformation (CCM067, CCM095) and patients with normal cerebellum and posterior fossa (CCM001). A: sagittal midline T1-weighted images. B: axial T2-weighted images. <ref name=”PMID PMC3667004”><pubmed> PMC3667004</pubmed></ref>

==Joubert Syndrome==
Joubert syndrome (JS) is described as a rare inherited genetic disorder characterised by lack of muscle coordination, intellectual disability, respiratory disturbances and abnormal eye movement <ref name=”PMIDPMC2913941”><pubmed>PMC2913941</pubmed></ref>. On neuroimaging, the cerebellar vermis is identified to have gone through hypoplasia (underdevelopment) or dysplasia (abnormal development) <ref name=”PMID22108217”><pubmed>22108217</pubmed></ref>. It is also described as the "molar tooth sign" on brain imaging, which the "molar tooth" shaped is caused by the defects in the midbrain-hindbrain development.

[[File:JoubertSyndrome.jpg|225px]]

Brain Imaging of Joubert Syndrome: Cranial MRI showing “molar tooth sign” (arrows)<ref name=”PMIDPMC3896311”><pubmed>PMC3896311</pubmed></ref>

==Chiari Syndrome I-III==
Chiari Syndrome I-III is when the structures within the posterior cranial fossa protrude into the spinal canal <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref> which can affect the development and functioning of the cerebellum in the long term. Chiari Syndrome can be classified into four types. The downward shift of the cerebellar tonsils to beneath the foramen magnum is type 1 and the downward movement of the vermis, medulla oblongata and pons with the fourth ventricle is type 2 <ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>. When majority of the cerebellum lies in the foramen magnum it is type 3 and when it is completely in the foramen magnum (and therefore cannot develop normally) it is type 4<ref name=”PMID18762395”><pubmed>18762395</pubmed></ref>.

[[File:ChiariMalformation.jpg|225px]]

Cerebellar tonsils herniation on magnetic resonance imaging: Chiari malformation type I<ref name=”PMIDPMC4279813”><pubmed>PMC4279813</pubmed></ref>

==Rhombencephalosynapsis==
Rhombencephalosynapsis is a rare cerebellar defect whereby there is dorsal fusion of the cerebral hemispheres, fusion of dentate nuclei and superior cerebellar peduncles as well as the agenesis of the cerebella vermis <ref name=”PMID18155944”><pubmed>18155944</pubmed></ref>. Like other mentioned abnormalities there is development delay because of the underdeveloped cerebellum.

[[File:Rhombencephalosynapsis.jpg|225px]]

Partial Rhombencephalosynapsis with fused upper parts of the cerebellum<ref name=”PMIDPMC3447431”><pubmed>PMC3447431</pubmed></ref>

=Future Questions=

=Glossary=
{{Glossary}}

=References=
<references/>

File:Neural Circuit in the Cerebellum.jpg

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==Neural Circuit in the Cerebellum==
Cerebellar neuronal circuits (A): Representation of zebrafish cerebellar neurons (B): Sagittal section of the adult zebrafish cerebellum (C): Zebrafish cerebellar structure schematic representation <ref><pubmed>21309081</pubmed></ref>

==References==
<references/>

==Copyright==
Request was permitted when John Wiley and Sons were contacted. License was granted through Copyright Clearance Center’s RightsLink® service.

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File:Granule Cell and Purkinje Cell Migration.png

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=Granule Cell and Purkinje Cell Migration=

Granule cell (yellow) and purkinje cell (green) migration timetable in mouse cerebellum. Top shows sagittal sections of entire cerebellum. Bottom shows movement of individual cells at interface of EGL and purkinje cell layer.<ref>Jerry Vriend, Saeid Ghavami, Hassan Marzban The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma. Mol Brain: 2015, 8(1);64 PubMed 26475605</ref>

==Reference==
<references/>

==Copyright==
© 2015 Vriend et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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{{ANAT2341Project2017discussion}}



=Project Starting Places=
[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:15, 14 August 2017 (AEST) OK Group 6 below are some starting places.

{{Neural Links 2}}

PubMed Searches: [http://www.ncbi.nlm.nih.gov/pubmed?term=Cerebellum+Development ''Cerebellum Development'']

BMC Dev Biol Search: [http://www.biomedcentral.com/bmcdevbiol/search/results?terms=Cerebellum+Development ''Cerebellum Development'']

Cerebellum: links between development, developmental disorders and motor learning; [http://journal.frontiersin.org/article/10.3389/fnana.2012.00001/full]

Cellular commitment in the developing cerebellum [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290586/]

Recent papers

<pubmed limit=5>Cerebellum+Development</pubmed>

==Neural Development==
(z5114433)
will fix referencing stuff later #ceebsrn

Neural development is one of the earliest systems to begin and the last to be completed after birth due to its highly complex structure. The first step in neural development occurs at the end of week 3 and involves the folding of the neural tubes to form the cranial and caudal region of the embryo (''https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-26-embryonic-folding-and-flexion-of-the-embryo'') . There is a high chance of neural dysfunction and defects during the fetal neural development particularly due to the long development time frame and the need of certain nutrients such as folic acid to successfully close the tubes. Neural tube defects (NTDs) such as [[spina bifida]] and [[anencephaly]] can arise if the tubes do not close effectively.

=z5114433=
structure
time course
functional developing
what cells appear when

glial cells development

4th ventricle

Genes in abnormalities

pathway of development of cere cells
start of as neuroblast

=z5018156=
Things to remember:

Coordinates muscular activities - walking, crawling, writing

Embryo doesnt need the musuclar activities

Prenatal - neurons develop to carry out those activities later on

Postnatal - wiring up

Neural tube

Comes from pontine flexure - 4th ventricle -- the cerebellum develops into this space

Lamination of the cerebellum

https://www.ncbi.nlm.nih.gov/pubmed/19732611

https://www.ncbi.nlm.nih.gov/pubmed/21380713

Development: z5018156 - https://www.ncbi.nlm.nih.gov/pubmed/21295689

=Z5076158=
==Week 7 Work==
What I could add: Paramotal cells, molecular layer, what cerebellum connects to, how they are remodeled postnatally Kahals research
https://discovery.lifemapsc.com/library/review-of-medical-embryology/chapter-150-the-brainstem-metencephalon-fourth-vesicle-the-cerebellum - good reference
LARSONS HUMAN EMBRYOLOGY TEXTBOOK
The metencephalon gives rise to the pons and the cerebellum, the adjacent rhombic lips also contribute to the development of cerebellum. The pons functions to relay signals that link both the spinal cord and cerebral cortex with the cerebellum and the cerebellum is a centre for postural and balance control. Pontine nuclei relay information from cerebrum to the cerebellum.
The cerebellum is first recognized as a pair of thickened cerebellar plates or cerebellar primordia.
Adjacent rhombic lips gives rise to Cerebellar granule cells
Major portion of the cerebellum consists of a narrow median swelling called the vermis and this grows faster than the flocculonodular which were the primitive part of the cerebellum and therefore becomes the dominant portion of the mature cerebellum.
Folding:
Primary fissure deepens by end of third month and divides vermis and hemispheres into a cranial anterior lobe and caudal middle lobe. Lobes divide further into lobules due to development of transverse fissures. This fissure formation and foliation continues throughout embryonic, fetal and postnatal life and this is done to increase the surface area of the cerebellar cortex.
2 types of grey matter present:
- Internal deep cerebellar nucler
- External cerebellar cortex
4 deep nuclei and all output of the cerebellar cortex is relayed through these nuclei.
These nuclei and cortex are produced by a process called neurogenesis and neuronal migration
1. Dentate
2. Globose
3. Emboliform
4. Fastigular

4th month – germinal layers undergo cell division and this produces populations of cerebellar neurons.
• Ventricular layer – purkinje cells, golgi cells, basket cells, stellate cells
• Granule cells remaining from the cerebellar cortex (these arise from external germinal layer)
• External germinal layer – primitive nuclear neurons these migrate to form deep cerebellar nuclei
==Week 8 Work==
PAPER 1995
Cerebellum – about:
It consists of 3 layers with 2 principal classes of neurons
Granule cells studies of naturally occurring mutations and targeted gene disruption that block discrete steps in development of this region
Development of anterior portion of neural tube involves the formation of 3 brain vesicles:
1. Prosencephalon
2. Mesencephalon
3. Rhombencephalon
Division of rhombencephalon into metencephalic vesicles and myelincephalic vesicles (this forms in day 9)
Failure of neural tube closure creates gap along the dorsal aspect of the neural tube, which bows into a mouth-like structure as the tube bends to establish the pontine flexure.
Further deepening this newly formed pontine flexure, bringing the mesencephalon (midbrain) closer to the primordium of the cerebellum (metencephalon); anterior aspects of the myelincephalon (brainstem) fold underneath developing the cerebellum plate.

Cells fated for cerebellum are derived from both the mesencephalon and metencephalic vesicles (rhombencephalon). Neuroepithelium of the mesencephalon generated majority of the cells in the cerebellar cortex: V-like area of mediodorsal aspect of the anlarge arose from a caudal movement of cells from the mesencephalon.

PAPER 2014
Cerebellum has a very basic structure:
• Monolayer of inhibitory purkinje cells sandwiched between a dense layer of excitatory granule cells
• Subpiled molecular layer of granular cell axons and purkinje cell dendritic fibres
Granule cells receives inputs from outside the cerebellum and project to the purkinje cells, the majority of which then project to a variety of cerebellar nuclei in the white matter.
The area designated for the cerebellum to reside (anlage) during development was located between hindbrain and midbrain. Regulation of patterning in this early stage (E9) of development shows to be particularly important for development of the uniquely mammalian midline expanded region of the cerebellum, “vermis”.

Specific cell types are allocated along the dorsoventral axis. For glutamatergic cells of cerebellum, remarkably prolonged establishment and an important dynamic process that takes place at most dorsal interface between neural and non-neural roof plate tissue, the rhombic lip. This phase generates the basic dichotomy between GABAergic and glutamatergic cell types that underlies the conserved Purkinje-Granule cell circuit.
Cell type allocation proceeds a third, distinct temporal phase of development that extends into early prenatal (up to 2 years). In this phase, the principal derivative of the rhombic lip, the granule cell precursor, accumulates over the surface of the cerebellum and undergoes further rounds of symmetric division in a process of transit amplification that exponentially expands its numbers.
The anlage of the cerebellum is a product of mechanisms of segmentation that establish iterated rhombomeric subdivision within the hindbrain just after neural tube closure.
All cells of the cerebellum arise from dorsal rhomomere, a region definitively classified by absence of the expression of Otx and Hox genes. Majority of cerebellum arises from metencephalic (rostral) hindbrain.

==Peer Review to other groups==
===Group 1===
The layout is looking very good, pictures could be a little smaller. I like the choice of headings, they explain well what is going to be talked about. I feel like you need to add headings like animal models and current research needs to be fixed but I’m sure that’s what is intended. I have some minor points for some of the headings:
Early development:
Spelling: Rhomboncephalon, and the instead of three at the beginning of a paragraph. Overall this heading was covered well
Development of cerebral cortex:
With images, you can add figure titles and this could make your page flow better!! Maybe expand a bit more on the key developmental zones in the human cortex, a brief explanation of what happens could help. The table is very well explained, however for E50-55 I can’t see a reference for all the information, also for the picture in the table for E50-55, you haven’t copied the copyright information so you should add that so it can be used in the page and also add the student template. I really like the drawn picture, but again a figure description would be helpful. This section is very well done.
Anatomy of the cerebral cortex
Some great points but needs to be broken up into paragraphs. Your Wikipedia link for the image is a good image however you should find the original, I recognize it from Cajal’s drawings so I think it could be in a paper about the cerebellum with Cajal. You have good ideas for this heading, also maybe add another image.
Functions of the cerebral cortex
For functional areas, I think a 2 sentence description of each area would be good and maybe a picture for reference.
Abnormalities
Intext referencing would be better. For images, add the student template to each!! Im not entirely sure how I feel about the youtube screenshots as images, maybe use one but try and find some in research articles aswell.
Overall, I think you’ve done a really good job at summarizing abnormalities.

===Group 2===
I believe the headings chosen cover a sufficient amount of points you need in order to describe kidney development!
Referencing needs to be changed, its easy to use the code <ref> <pubmed>INSERT PUB MED ID</pubmed> </ref> and that automatically makes a reference for you!
When describing position, explain what retroperitoneal means, its not commonly known and also Thoracic 12 (T12) so people know what T12 refers too.
For images, you need to find the copyright information and reference them properly, Mark has step by step instructions on what needs to be included in the image description. There aren’t many references in the first section of the page, it would benefit if you included some. Under nephrogenesis, point 3, you can find the articles pubmed ID and add the reference in that way instead of manually doing it.
For developmental abnormalities, I feel like this could be explained better, it gets technical straight away and this can become quite confusing.
Current research and questions need to be worked on but I’m sure that’s whats intended.
Overall I think the content on this page is very relevant to kidney development and it was interesting to read. The two major things you should fix are image copyright and references and intext referencing.

===Group 3===
Introduction is very good and explains a lot. Under the heading “Primary heart field and heart tube formation” – the reference at the bottom should be removed.
Secondary heart field and cardiac looping: First sentence doesn’t really make sense, maybe switch it up a bit.
Under current research and findings you have labelled a figure figure 1, when it is not the first figure in your wiki page, seems a little confusing. Images also don’t have appriopriate copyright info, description and referencing. Also figure 2 is placed right in the middle of the sentence, maybe put it to the right so it doesn’t interrupt reading.
Information could be formatted better under the heading atrial septal defect! Maybe some subheadings for the different defects? Same goes with the ventricular septal defect, its easier to read when things are broken up. Glossary is very good!

All the information written on your page is very well written and easily understood.
Images could be labelled better, add a figure to each of them as when you are referring to figure 1 and 2 in your writing, the images aren’t labelled so its hard to tell what image you are referring to.
With references, I don’t like how there is a bunch at the end of some headings? Could be because you still need to read them but looks messy.
There is an overwhelming amount of information, so good job on doing so much research but it was quite tedious to read, not sure if this much information is needed? But it is very hard to fault your wiki page so this might be a bit picky.

===Group 4===
Reading through this page was very interesting and informative however I have a few points that could be adjusted to improve on your page. When inserting an image, adding a figure and brief description on the images would be useful. The timeline is good but there is no reference so it definitely needs one. When reading through all the other tables, references need to be used more as it isn't that easy to figure out what articles you have used to get your information. More work needs to be done to fill the headings under development of eye components and if more images were added it would be useful. Abnormalities could have a bit more of an explanation written as well. Your wiki page is looking good, I would suggest a heading on animal models would provide some good information and fit well with your page! I also haven’t read anything that tells us about signaling, this should have its own heading and should be explained quite well as it is an important part of development. With your figures, it would be nice if you referred to them throughout your text more, and integrated them with the headings. Although this page is a work in progress, the information written is useful and easy to understand.

===Group 5===
This wiki page is very informative and good to read! When reading I noticed that the images don’t have a figure number, although this isn’t necessary, it can make it easy to refer to figures in text and therefore explain them better. For the heading lung histology, you can add proper dot points by adding an asterix before the information, this will make your page present better. Both headings future questions and current research need to be finished as they are incomplete. Using self drawn pictures makes your page easy to follow and understand, this is a great feature of your page. Copyright information is added well for the most part, however I found some images under the heading “Developmental signaling processes” which didn’t have any copyright information or an appropriate description, also make sure the student template is added at the end of every image description. I particularly enjoyed the timeline, it is very well written and is easy to understand. Good job on the project thus far.

=z5113034=
Vasculature of cerebellum originates from vertebral arteries and the arteries that arise from it.

Metencephalon; temporary structure that differentiates into pons and cerebellum ventrally and dorsally respectively.

Current Research

Key discoveries during research of cerebellar development

=Topic Selection=
Hi group! I am personally interested in the development of the heart! Also, are you guys happy to exchange details after the lab tomorrow? - z5018156

Hi! Im happy to share details! And yeah heart would be interesting, but I was also thinking maybe the ear? that could be cool

Hey, yeah I was thinking the heart- I did a course on it last semester, but i also feel its quite generic and the other groups would do something similar. Shall we wait until the end of prac and find each other? Call out number 6 LMAO (z5114433)

Hey all! I'm pretty open about topics but I was leaning towards the eye? Unless that's too close to optom, (and it might be a popular subject too?) I'm fine with anything. Let's find each other after prac! -z5113034

The ear sounds good as well as the eye, theres also the lungs as well! We can just make a list and then decide as a group! - z5018156

=Peer Review=
This page is very informative, well set-out, and easy to follow and read. The information is well-referenced and the images have a description, the correct Copyright, however some lack the appropriate Student Image template. The "Key Historical Discoveries" and "Cell Signaling in Cerebellar Development" sections could be broken up with relevant images. Other images I find are too large and could be made smaller. The smaller amount of information above the "Introduction" would flow better if it was all included as one introductory paragraph. The images in the "Abnormalities" section could include a small description directly under them to describe the image and make it more uniform with the other images on the pages. Reference list is extensive and done very well. The page could be improved by including a "Future Research Questions" section. Overall very hard to fault!

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The information is really well written and informative. The use of images is really good, especially with the description and when they have been included in the table. The section on the Historical Discoveries is a really interesting part and adds a good amount of background information to the cerebellum. Maybe add a table for the glossary section part that just relates to the terms relating to the cerebellum. Make sure that all references are referenced properly, not just the addition of the links. Overall, a really good wiki and the information is understandable and very well done.
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This page was easy to follow and had good flow, with relevant headings and subheadings relating to the development of the cerebellum. Basic anatomy of the cerebellum contained a good amount of information, which provided relevant background knowledge before jumping into the development. Images were nicely chosen and was very relevant to the content, and they were also cited properly. There were some sections under Anatomy of the cerebellum that were related to the development, so it would be better to move it into the "Development" section to further improve flow. The table of "Cerebellum Developmental Weeks" was very clever especially with the images used. There is a vast amount of references used, and they were done properly. A "Further questions" section is needed to address any research gaps as well as explore more information on the Cerebellum. So far, well done!

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There is a good introduction into the cerebellum which is also connected to the page and what the page will explore. The “basic anatomy” subheading is nice and succinct with minimal text and clear diagrams that clearly represent the anatomy of the cerebellum. The “Vasculature” subheading also provides a good overview with a simple diagram to complement. The only thing I find a bit odd about all the subheadings under “basic anatomy” is that I feel as though we go from the adult human anatomy of the cerebellum into embryological anatomy of the cerebellum. I think it might serve you better to split these up or just rearrange/rename your subheadings a bit. The reason for this is because the cerebellum is quite complex so I think it would help to absorb the information.
The “cerebellum development” is a good and descriptive subheading with a good use of diagrams. Since there is quite a big chunk of text, it would probably be better if you broke it down where you could. So, for example, where you say: “there are two types of grey matter in the cerebellum…” you could easily use dot points. It just helps with readability.
The “cellular migration” subheading is very good and the diagram you found is a great representation of it. I like that you added images to complement each week of development in your first trimester timeline. If you can do the same for your second trimester timeline that would be great. Your “key historical discoveries” subheading could use some images (even if it is of the people who made the discoveries). You chose a good number of abnormalities to explore in that last section. You might want to add another section for “future questions” just to hint at what more we need to learn about cerebellum development. You have a solid, long list of references.

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Really good project page. The page goes through almost everything required for the project. You need a section about Further Questions and Current Research. The project is really well written and easy to understand. There is a good introduction giving the reader an idea of what to expect from the project page and good use of pictures giving a basic understanding of the anatomy of the cerebellum. There is a lot of use of figures and tables, which makes it easier for the reader to understand the subject. Most of the figures have a figure number and text, this also makes it easier to get a quick view of what the text refers to. The layout of the page is also comfortable to go through, but I do think the title Cerebellum in blue is a bit disturbing. There is good use of references.

*It seems like you have mixed the context in '''Basic Anatomy of the Cerebellum section''' and the '''Cerebellum Development'''. During the 'Anatomy section, you start describing the developmental origin, which I think would fit better in the Developmental section.
*The first section in the '''Cerebellum Development''' has a lot of text. Maybe you can make some subsections to split of the text and makes it more comfortable to read.
*The '''Cerebellum Developmental weeks table''' is really good and has good use of pictures. But the format makes it really big. Maybe you can do this part in a different way, so it does not take that much space. For the table about the second trimester, it would be a good support for the reader to add pictures to this table too – like the first-trimester table.
*The '''Key Historical Discoveries''' has a lot of text. Maybe you can add some pictures or change the layout a bit.

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Very efficient page in its structure and attention to detail throughout the text. Subheadings are easy to follow and did not cause any confusion. The use of diagrams and images are relevant and accompany the text well and are referred to as figures which elevated the efficiency, however, inconsistencies in labelling the images are evident with many images lacking the figure number such as “diagram of a 2 day old…”. This would ease the process of referring to images throughout the writing and improve the reading experience. There is no section on current research or further questioning which is a shame as it is an interesting aspect of reading these pages and I feel it would add an up to date relevance to the overall page. Expansion on the abnormalities mentioned under the subheading is required as only a few are mentioned and not discussed. Some of the technical terms were difficult to follow so definitely a glossary would fix this. Referencing seems to be quite consistent throughout for the most part, however some areas are lacking acknowledgement to resources. Overall, an informative page which demonstrates a thorough understanding of the cerebellum.

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Overall, this team's wikipage was really informative. They were detailed yet not too much information was given. There was a good balance with text and pictures. The pictures chosen were all of good quality as well with appropriate description, referencing and copyright information provided. The introduction was a very good brief of the entire page and explained what was to be expected. In the basic anatomy of the cerebellum, the subheadings were really well-defined. However, maybe neural development should be shifted to the developmental section instead. This section was well referenced. I like the use of the table to describe the cerebellum developmental weeks. The images used were really helpful in visualizing what was happening in those weeks. In the abnormalities section, it was short and concise with good picture. Maybe the caption of the photos could be placed together with the photo such as those in the table. This could make the photos look neater. Overall I find that this wikipage was well done, it had a good amount of text and photos and the references were all properly included.

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Overall, I think this project page is really good and well done to the team. I think the headings and subheadings flow easily and there is a good arrangement of information. There is a good amount of referencing and the images have copyright statements and brief descriptions. For the “Neural Development” subsection, instead of placing it under the anatomy of the cerebellum, I think you should move it down to the development section as it has more relevance to that. I think the Cerebellum Developmental weeks should be shifted to before the description on cerebellum development. This way, the readers can have a general idea on the development and its stages before going through he description because the description is quite content heavy and if we were to read that first, its quite confusing and hard to understand. For the key historical discoveries, maybe you could use a table with two columns where one column can be the name of the discoverer and the other column could be a brief description. The abnormalities section was done well.

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Overall this project is very extensive and appears to almost be complete. The structure and lay out is clear and easy to follow. The numerous tables and diagrams are very engaging. The material seems to be relevant, informative and well-referenced. I think the you could combine the first section into the introduction as it is confusing to have two introductory sections. Also the blue title could be larger and at the top of the page to highlight the overall topic of the project. The sections of ‘cell signaling in cerebellar development’ and ‘key historical discoveries’ and ‘animal models’ are not very engaging to read as they are just large chunks of text and perhaps images, videos or collapsible windows could be used to break them up and make them more attractive. Despite these minor suggestion, your project is extremely well done!

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The introduction and the information above the introduction is really good, however, I think it would be better if you merged these into one as it sort of seems like two introductions and doesn't flow very nicely, even though what you're saying is really good. The basic anatomy was really good, especially with the images and the reference to them. The microanatomy information is good however would be better if you added images like you did in the anatomy. The cerebral nuclei table is good, however, I think its distracting the description in the centre, just have it normal and don't centre your text. Place the information about the primary and secondary brain vesicles above their images and then refer to the images. Some of your sections, for example, cell signalling or key historical developments, are really wordy and hard to keep a focus so maybe split them up with images, videos, or tables. The rest of the page looks really good, maybe just add some more information to the abnormalities as some are only a sentence or so. The page could also benefit from using a video or two. Referencing is good.

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It was really good that the structure and function of the cerebellum was explained in a succinct way in the beginning. The introduction repeated the word 'hence' a few times, maybe it's better to modify it into bullet points, in a similar way when lecturers provide a slide on the lecture overview. Appropriate images were added as well as figure labeling. Copyright approval was also provided for the images and were referenced appropriately. The use of tables was also appropriate in some of the topic sections. Images were also in appropriate sizes that avoided covering the while page. The page was very detailed as well. Some sections like "Cell Signaling" was a bit lengthy, images would be nice. It was good that reputable journal articles were used for the project, proper in text citations superscripts were also done properly. However, revise the reference list because some were left as links and the list did not have a consistent reference format. But overall, the page looks almost complete.

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This page seems to have the one of the best organizations. All the sub headings needed for the project are included and completed (minus further questions). The introduction is a nice addition as it gives a roadmap to your page. The entire Basic Anatomy is informative and sectioned nicely into the most important topics--some of the images may be a bit too large however. I like that the information for the first and second trimester is separated, instead of clumping it all together. Cerebellum development, cell signaling, and key historical discoveries have a lot of text and might need some diagrams or tables to break up the text. Also it would help to put the key historical discoveries at the beginning so that the reader knows how it led to the information we know today. The neural development section should be moved below microanatomy and before early brain vesicles since it leads into that section. The

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This peer review is based on the relevant dot points of the ‘Group Assessment Criteria’, as well as subheadings suggested by Mark. This information can be found on the student page.

{| border="1" align="left"
|-
|Criteria
|Strengths
|Weaknesses
|-
| 1. The choice of content shows a good understanding of the topic area
| The ‘basic anatomy of the cerebellum’ section is written well and in detail. It provides a solid introduction to the wiki page, as well as background information that assists in understanding other sections. The chosen visual aids enhance the written information, and allow the reader to visualize some of the more complex ideas.

The ‘signaling processes’ and ‘key discoveries’ sections were both well addressed, with the information being expressed clearly.

The developmental timeline provides a nice summary of cerebellum development, especially throughout the first trimester. The accompanying images are both relevant and useful in understanding the text.

Overall, the wiki page is structured well, with the chosen sub headings making the page easy to navigate.
| The wiki page lacks some important areas of information, including:
*‘Future questions’ regarding development of the cerebellum
*‘Current research’ in relevant fields
*A glossary of terms

Some sections could also be improved. The ‘animal models’ section has been addressed minimally, with only one example being provided. Try to include several more examples of animal models. In addition, the ‘abnormalities’ section lacks detail for some of the examples (see ‘rhombencephalosynapsis’).

Some areas of the wiki page would benefit from visual aids, such as the ‘animal models’ and ‘signaling processes’ sections.
|-
|2. Content is correctly cited and referenced
|Most areas of the wiki page contain some degree of referencing. ‘Cell signaling in Cerebellar development’ was the most well-referenced section.
The reference list is extensive and is mostly correct. The majority of the sources in the reference list are peer-reviewed primary research articles.

Most of the images on the page have been referenced correctly (see all images in the ‘abnormalities’ section).
|Referencing throughout the wiki page is inconsistent. Some areas contain minimal in-text citations (see ‘cerebellum development’) and other sections lack referencing entirely (see weeks 3-6 of the developmental timeline). Remember to cite any and all text that is unoriginal in regard to idea or structure.

Some of the images on the wiki page have not been referenced correctly (see ‘lateral view of embryo central nervous system at 5 weeks’). In addition, the copyright section of figure 4 states that ‘copyright has been requested’; avoid uploading images until after the copyright request has been approved.

Some references have been repeated in the reference list (see references 47 and 48).
|-
|3. The wiki has an element of teaching at a peer level
|The information presented on the page is written at a level suitable for peers.

Many of the chosen images and tables help clarify some of the more difficult concepts discussed on the page.
|Many of the acronyms and terms used in this assignment are either poorly explained, or not explained at all. Remember to include relevant definitions in the ‘glossary’ section of the page.

The page currently lacks student-drawn diagrams; try to include some for the final submission (and remember to cite the source of inspiration).
|-
|4. Relates the topic and content of the Wiki entry to learning aims of embryology
|The wiki page addresses most of the relevant learning aims of embryology, including embryonic development, a developmental timeline, signaling processes, key discoveries, animal models and congenital abnormalities.
|There are some sections relevant to the learning aims that have not been included, such as ‘current research’ and ‘future questions’.
|-
|5. The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic
|Most of the content on the wiki page has been researched well, particularly the ‘basic anatomy of the cerebellum’ and ‘cerebellum development’ sections.

The reference list contains a large variety of reliable sources of information (i.e. primary research articles). This demonstrates that this topic has been well researched.
|Links to other wiki pages on the UNSW embryology wiki have not been included. Try linking some sections of the page to other wiki entries, such as ‘lecture 4 – week 3’ or ‘lecture 5 – ectoderm’.
|}
--- 
Strengths: 
• The authors of this wiki page have included a variety of topics relevant to the development of the cerebellum. Topics range from the normal anatomy of the cerebellum, abnormalities, and the normal developmental process to animal models. Thus it is evident that criteria 1 has been satisfied which is excellent! 
• A broad variety of tables and images have been utilized within this wiki page which is another excellent feature that has been included. Not only has this enhanced the presentation of the page, but the images serve as a visual aid in assisting in the explanation of certain concepts to peers (particularly those who are visual learners) (criteria 2 and 4 satisfied). For example the use of images was utilized to help simplify the explanation regarding the vesicles that development. 
• It also appears that authors have included a broad variety of references in-text to cite all information utilized. Most source utilized appear to be recent and all have been correctly cited (criteria 3). 
• The authors of this page have also explored evidence of significant research relating to basic and applied sciences that extends beyond the formal teaching activities (criteria 5) by exploring avenues including animal models and how the use of animal models have contributed to our understanding of the cerebellum. Authors of the page have also explored abnormalities of cerebellar development which was excellent 
Areas of improvement: 
• In order to improve, authors may wish to expand on different animal models utilized.
• The authors of this wiki page may also wish to utilize videos as another visual tool to aid in the presentation of content included. 
• Another area of improvement would be to cite sources that are of a more recent date, rather than citing sources from the 1970s. The reason being is that such sources may include information that is currently outdated, thus the page may be providing inaccurate information about cerebellar development. 
• Authors of the page may have also covered certain topics in greater depth. For example the heading titled “Cell signaling in cerebellar development” may have been subdivided into different types of genes and signaling factors involved in cerebellar development. Authors may then elaborate on each gene/signaling factor. This will help enhance presentation whilst also improving the readability of the information presented.

Grade: DISTINCTION

General Comments:
Most sections of this wiki page have been presented at a high standard. There are only a few areas that could do with some improvement.