Neural - Cerebellum Development
|Embryology - 19 Aug 2019 Expand to Translate|
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- 1 Introduction
- 2 Some Recent Findings
- 3 Development Overview
- 4 Early Brain Vesicles
- 5 Embryonic Cerebellum
- 6 Fetal Cerebellum
- 7 Third Trimester
- 8 Cerebellar Cells
- 9 Precerebellar Neurons
- 10 Cerebellar Nuclei
- 11 Cerebellar Pathways
- 12 Molecular
- 13 Abnormalities
- 14 References
- 15 Terms
- 16 Additional Images
- 17 Glossary Links
The cerebellum (Latin, ‘little brain’) major role is in role in sensory-motor processing that in the adult human contains more than half of all the brain's neurons. The adult cerebellum anatomy consists of three parts, the vermis (median) and the two hemispheres (lateral), which are continuous with each other.
The adult human cerebellum contains 69,030,000,000 ± 6,650,000,000 (sixty-nine billion thirty million) neurons and 16,040,000,000 ± 2,170,000 other cell types.
- "For every neuron added to the cerebral cortex in evolution, four neurons are added to the cerebellum."
|cerebellum comes the historic histological studies and staining of Ramón Cahal (1852 - 1934) and Camillo Golgi (1843 - 1926). Cahal was a Spanish researcher who used the then new histology Golgi staining techniques to identify the cerebellum cellular structure. His work was a turning point in our understanding of the structure of the brain, that until then had been described as a "syncytium" and not consisting of discrete cellular elements. For this research and other work on defining the structure of the brain he, along with Camillo Golgi (1843 - 1926), received the 1906 Nobel Prize in Medicine.
Neural development is one of the earliest systems to begin and the last to be completed after birth. This development generates the most complex structure within the embryo and the long time period of development means in utero insult during pregnancy may have consequences to development of the nervous system.
Within the neural tube stem cells generate the 2 major classes of cells that make the majority of the nervous system : neurons and glia. Both these classes of cells differentiate into many different types generated with highly specialized functions and shapes. This section covers the establishment of neural populations, the inductive influences of surrounding tissues and the sequential generation of neurons establishing the layered structure seen in the brain and spinal cord.
Some Recent Findings
|More recent papers|
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.
Search term: Cerebellum Development | Cerebellum Embryology | Bergmann glia | Dentate Nucleus Development | Fastigial Nucleus Development | Interposed Nuclei Development | Vestibular Nuclei Development | Dandy-Walker Syndrome | Foliation Defects | Joubert Syndrome | Pontocerebellar Hypoplasia | Medulloblastoma
|These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.
Neuralation begins at the trilaminar embryo with formation of the notochord and somites, both of which underly the ectoderm and do not contribute to the nervous system, but are involved with patterning its initial formation. The central portion of the ectoderm then forms the neural plate that folds to form the neural tube, that will eventually form the entire central nervous system.
- Early developmental sequence: Epiblast - Ectoderm - Neural Plate - Neural groove and Neural Crest - Neural Tube and Neural Crest
|Neural Tube||Primary Vesicles||Secondary Vesicles||Adult Structures|
|week 3||week 4||week 5||adult|
|prosencephalon||telencephalon||Rhinencephalon, Amygdala, Hippocampus, Cerebrum (Cortex), Hypothalamus, Pituitary | Basal Ganglia, lateral ventricles|
|Diencephalon||Epithalamus, Thalamus, Subthalamus, Pineal, third ventricle|
|mesencephalon||mesencephalon||Tectum, Cerebral peduncle, Pretectum, cerebral aqueduct|
- 6 weeks (CRL 12–16 mm) - anlage of the cerebellum was first identified as a pair of thickenings on the lateral site of the alar plate that faced the fourth ventricle.
- 7-9 weeks (CRL 28 mm) - rhombic lip (a pair of thickenings of the alar plate) protruded dorsally, bent laterally, extended ventrolaterally and fused with the medially located midbrain. During that process, the primitive choroid plexus appeared to become involved in the cerebellar hemisphere to form a centrally located eosinophilic matrix. At that stage, the inferior olive had already developed in the thick medulla. Thus, the term 'bulbo-pontine extension' may represent an erroneous labeling of a caudal part of the rhombic lip. The cerebellar vermis developed much later than the hemisphere possibly from a midline dark cell cluster near the aqueduct.
- 11–12 weeks (CRL 70–90 mm) - cerebellar hemisphere became as thick as the mid- brain. In the hemisphere, a laminar configuration became evident but the central eosinophilic matrix remained pres- ent. Fissures of the future vermis appeared in the midline area (Fig. 6): the developing fissures provided island-like structures in horizontal sections. The hemisphere and ver- mis, including the surfaces of the fissures, were covered by the external germinal cell layer.
- 15–16 weeks (CRL 110–130 mm) - cerebellar hemisphere contained the primitive dentate nucleus. The nodule and flocculus were identified, vermis became as thick as the hemisphere and it accompanied several deep fissures.
Early Brain Vesicles
|Primary Vesicles||Secondary Vesicles|
|week 3 to 4||week 5 +|
|This midline section through the upper half of the embryo shows the 3 primary vesicle regions (unlabeled image).
The cerebellum will develop from the hindbrain (rhombencephalon) region.
Adjacent to the forth ventricle (see as the enlarged dark dorsal region).
Human Embryo (Carnegie stage 13) 28 - 32 days.
|Carnegie stage 21|
|lateral view (scale bar 1 mm)||Median view|
|Plane A (midline)||Plane B (medial)|
|Plane C (lateral)||Plane D (most lateral)|
Developing human cerebellum preterm
A greater EGL cell density and reduced EGL thickness were reported in preterms with ex-utero exposure, as compared to their age matched stillborn controls.
These drawings of cerebellar cells were based upon electron micrograph images from the rat cerebellum.
Gray H. Anatomy of the human body. (1918) Philadelphia: Lea & Febiger.
- "The cerebellum is developed in the roof of the anterior part of the hind-brain (Figs. 649 to 654). The alar laminæ of this region become thickened to form two lateral plates which soon fuse in the middle line and produce a thick lamina which roofs in the upper part of the cavity of the hind-brain vesicle; this constitutes the rudiment of the cerebellum, the outer surface of which is originally smooth and convex. The fissures of the cerebellum appear first in the vermis and floccular region, and traces of them are found during the third month; the fissures on the cerebellar hemispheres do not appear until the fifth month. The primitive fissures are not developed in the order of their relative size in the adult—thus the horizontal sulcus in the fifth month is merely a shallow groove. The best marked of the early fissures are: (a) the fissura prima between the developing culmen and declive, and (b) the fissura secunda between the future pyramid and uvula. The flocculus and nodule are developed from the rhombic lip, and are therefore recognizable as separate portions before any of the other cerebellar lobules. The groove produced by the bending over of the rhombic lip is here known as the floccular fissure; when the two lateral walls fuse, the right and left floccular fissures join in the middle line and their central part becomes the post-nodular fissure."
Researcher timeline based on a recent review on cerebellum
- Rolando - role in movement control
- Flourens - role in movement coordination
- Purkinje (1837) - histology of the cerebellar cortex
- Luciani (1891) - cerebellum has a tonic facilitating effect on central structures
- Bolk (1906) - localization for coordinating action on the motor system (medio-lateral organization)
- Cajal - histology of cortex circuitry
- Eccles and Ito - inhibitory interneurons and the Purkinje cells, excitatory connections of mossy and climbing afferents and granule cells
- Babinski and Holmes - anatomoclinical insights
- Marr and Albus - theories involving cognition and emotion
- Leiners and Dow
- Magnus - cerebellum no role in body posture
Precerebellar neurons (PCNs) are born in the hindbrain alar plate in the specific region called the rhombic lip (for review see). From there they migrate by a process termed nucleokinesis, extending a cytoplasmic process then move their nucleus.
In recent years a number of different chemotactic positive and negative factors have been suggested to have a role in driving the guided migration of these cells. Many signals are thought to be mediated through the Rho family GTPases links to the cytoskeleton.
|Most medially located of the cerebellar nuclei.||Receives input from the vermis and cerebellar afferents that carry vestibular, proximal somatosensory, auditory and visual information.|
|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.|
|Largest of the cerebellar nuclei. Lateral to interposed nuclei.||Receives input from lateral hemisphere and cerebellar afferents that carry information from cerebral cortex.|
|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.|
|(A) Regions that send input to the cerebellum.
|Cerebellum connections to the brain and spinal cord (mouse).|
- Calm1 - signaling pathway is essential for the migration of mouse precerebellar neurons.
- Merlin - impacts on cerebellar pre- and post-synaptic terminal organisation, not the overall cerebellar development.
- sonic hedgehog - signaling by Bergmann glia is required for proper cerebellar cortical expansion and architecture.
|Dandy-Walker Syndrome/Malformation (DWS) is a cerebellar hypoplasia and upward rotation of the cerebellar vermis with ventricular enlargement (cystic dilation of the fourth ventricle). Named in 1954 after the earlier identification by Walter Dandy (1914) and Arthur Earl Walker (1942), two USA neurosurgeons.
Walter Dandy (1886 – 1946) Arthur Earl Walker (1907 – 1995).
International Classification of Diseases Q03 Congenital hydrocephalus Incl.: hydrocephalus in newborn Excl.: Arnold-Chiari syndrome (Q07.0) hydrocephalus: acquired (G91.-) due to congenital toxoplasmosis (P37.1) with spina bifida (Q05.0-Q05.4)
Mouse Cerebellar Foliation Defects
(A–B) Midsagittal sections of newborn (P0) wild-type and Mdm2puro/Δ7-9 cerebella stained with H&E. (C–D) Superimposition of P0 (purple outline), P7 (blue outline), and adult (green outline) cerebella from wild-type (C) or Mdm2puro/Δ7-9 (D) mice. By P7, all four primary fissures, as well as two additional fissures, are evident in Mdm2puro/Δ7-9 mice. Moreover, even in adulthood, the mutant cerebellum does not reach the size or complexity of the wild-type cerebellum. Abbreviations are: prc, precentral; pc, pre-culminate; pr, primary; pp, prepyramidal; sec, secondary; pl, posterolateral fissures.
Joubert syndrome (Joubert-Boltshauser syndrome, Cerebelloparenchymal disorder 4, Cerebellar vermis agenesis) is a rare disease of the cerebellum. Identified as a ciliopathy, characterized by the absence or underdevelopment of the cerebellar vermis, that controls balance and coordination. There is also malformation of the stem, connecting the brain and spinal cord. A recent super-resolution microscopy study has shown that the syndrome is caused by disruption of the ciliary transition-zone architecture.  Ciliopathies are a class of cell abnormalities that can be caused by mutations in components of the cellular transition zone, a domain near the base of the cilium, that controls the protein composition of its membrane.
- hypotonia - weak muscle tone
- ataxia - difficulty coordinating movements
- hyperpnea - episodes of fast breathing (improves with age and usually disappears around 6 months of age)
- oculomotor apraxia - difficulty moving the eyes from side to side.
- language and motor skills
- mild to severe intellectual disability
- distinctive facial features - broad forehead, arched eyebrows, droopy eyelids (ptosis), widely spaced eyes, low-set ears, and a triangular-shaped mouth.
- Links: NIH - Rare Diseases
Pontocerebellar Hypoplasia (PCH) are very rare, inherited progressive neurodegenerative disorders with prenatal onset (for recent review see). The major features are: hypoplasia or atrophy of cerebellum and pons, progressive microcephaly, and variable cerebral involvement. There is a further classification of 7 different subtypes (PCH1-7) and there is prenatal testing for the related inherited mutations.
- PCH2, PCH4, PCH5 - Mutations in the 3 tRNA splicing endonuclease subunit genes.
- PCH6 - Mutations in the nuclear encoded mitochondrial arginyl- tRNA synthetase gene.
- PCH1 - Mutations in the tRNA splicing endonuclease, the mitochondrial arginyl- tRNA synthetase and the vaccinia related kinase1.
Medulloblastomas are the most common childhood primary central nervous system tumour. They are thought to arise in the developing cerebellum from the precursors of the granule cell.
A recent consensus paper on experimental neurostimulation of the cerebellum suggests that this may be a target for symptomatic alleviation a number of neurological conditions. These neurological and neuropsychiatric conditions include:ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia.
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- Poretti A, Boltshauser E & Huisman TA. (2016). Pre- and Postnatal Neuroimaging of Congenital Cerebellar Abnormalities. Cerebellum , 15, 5-9. PMID: 26166429 DOI.
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- Bergmann glia - a cerebellar radial glial population that in development act as scaffolds for the radial migration of granule cell precursors from the external germinal layer (EGL or outer granular layer) to the inner granular cell layer (IGL).
- cerebellar nuclei - clusters of glutamatergic and GABAergic neurons located in the cerebellar white matter that are the synaptic targets of the majority of Purkinje cells. Projection neurons within nuclei account for the output of the cerebellum. Cerebellar nuclei are often termed ‘deep’ although the designation is superfluous.
- External Germinal Layer - (EGL or outer granular layer) a developmental transient layer that is lost following granule cell migration.
- Granule cell - neurons in the internal granule layer that receive excitatory inputs from mossy fibres, that originate in the pons, medulla and spinal cord. These glutamatergic excitatory neutrons receive local inhibitory inputs from Golgi neurons. Granule cells axons are T-shaped and extend into the molecular layer synapsing on Purkinje cell dendrites.
- Inner Granular Layer - (IGL) granule neurons (granule cell) lies deep to the Purkinje cell layer.
- Purkinje cell - neurons located in the cerebellar cortex that receive excitatory inputs from granule cell parallel fibres and inhibitory input from climbing fibres of the inferior olive. These GABAergic inhibitory neurons axons mainly extend to the deep cerebellar nuclei, some axons also directly innervate hindbrain vestibular targets.
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|Embryology History | Historic Embryology Papers)|
Gray, Henry. Anatomy of the Human Body. Philadelphia: Lea & Febiger, 1918.
Bailey, F.R. and Miller, A.M. (1921). Text-Book of Embryology. New York: William Wood and Co. The Cerebellum
Cite this page: Hill, M.A. (2019, August 19) Embryology Neural - Cerebellum Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Neural_-_Cerebellum_Development
- © Dr Mark Hill 2019, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G