|A personal message from Dr Mark Hill (May 2020)
| I have decided to take early retirement in September 2020. During the many years online I have received wonderful feedback from many readers, researchers and students interested in human embryology. I especially thank my research collaborators and contributors to the site. The good news is Embryology will remain online and I will continue my association with UNSW Australia. I look forward to updating and including the many exciting new discoveries in Embryology!
Mesencephalon (midbrain) forms the adult tectum, cerebral peduncle, pretectum and cerebral aqueduct. In the adult, this region has functions associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and temperature regulation.
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.
The early central nervous system begins as a simple neural plate that folds to form a groove then tube, open initially at each end. Failure of these opening to close contributes a major class of neural abnormalities (neural tube defects).
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.
- Neural development beginnings quite early, therefore also look at notes covering Week 3- neural tube and Week 4-early nervous system.
- Development of the neural crest and sensory systems (hearing/vision/smell) are only introduced in these notes and are covered in other notes sections.
Some Recent Findings
- Review - Time for Radical Changes in Brain Stem Nomenclature-Applying the Lessons From Developmental Gene Patterns "The traditional subdivision of the brain stem into midbrain, pons, and medulla oblongata is based purely on the external appearance of the human brain stem. There is an urgent need to update the names of brain stem structures to be consistent with the discovery of rhomobomeric segmentation based on gene expression. The most important mistakes are the belief that the pons occupies the upper half of the hindbrain, the failure to recognize the isthmus as the first segment of the hindbrain, and the mistaken inclusion of diencephalic structures in the midbrain. The new nomenclature will apply to all mammals. This essay recommends a new brain stem nomenclature based on developmental gene expression, progeny analysis, and fate mapping."
Midbrain-Hindbrain boundary cad7 and cad20
- Autotaxin controls caudal diencephalon-mesencephalon development in the chick "RNA interference against ATX altered the expression pattern of Pax6-regualted genes, Tcf4, Lim1, and En1, implying that ATX is required for the maintenance of the regional identity of the caudal diencephalon and the diencephalon-mesencephalon boundary (DMB). Furthermore, ATX-RNAi inhibited neuroepithelial cell proliferation on both sides of the DMB. We propose a dual role of ATX in chick brain development, in which ATX not only contributes to the formation of caudal diencephalon as a short-range signal, but also regulates the growth of mesencephalon as a long-range signal."
|More recent papers
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.
- This search now requires a manual link as the original PubMed extension has been disabled.
- The displayed list of references do not reflect any editorial selection of material based on content or relevance.
- References also appear on this list based upon the date of the actual page viewing.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
More? References | Discussion Page | Journal Searches | 2019 References | 2020 References
Search term: Mesencephalon Development | Mesencephalon Embryology | Midbrain Development
|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.
See also the Discussion Page for other references listed by year and References on this current page.
- Otx2 and Otx1 protect diencephalon and mesencephalon from caudalization into metencephalon during early brain regionalization. "Otx2 is expressed in each step and site of head development. ...In rostral forebrain, neopallium, ganglionic eminences and hypothalamus in front of prethalamus develop; we propose that they become insensitive to the caudalization with the switch from the Otx2 expression under the AN enhancer to that under FM1 and FM2 enhancers. In contrast, the medial pallium requires Otx1 and Otx2 for its development later than E9.5, and the Otx2 expression in diencepalon and mesencephalon later than E9.5 is also directed by an enhancer other than FM1 and FM2 enhancers."
- Organization of the human embryonic ventral mesencephalon "The neurons in the ventral mesencephalon (VM) are organized into several nuclei consisting of distinct neuronal populations. These include the dopaminergic (DA) neurons of the substania nigra and ventral tegmental area, the oculomotor (OM) neurons that innervate the muscles controlling eye movement, and the reticular neurons of the red nucleus (RN) involved in motor control and coordination reviewed in Puelles (2007). We report that BLBP and LMX1A mark the floor plate and that FOXA2 is expressed in both the floor plate and basal plate of the human VM. The proneural transcription factors NGN2 and MASH1 are expressed in the ventricular zone of the human VM within and lateral to the floor plate. The post-mitotic DA neurons express TH as well as NURR1 and PITX3. ISL1 and BRN3A can be used to detect the cells of OM and RN, respectively. We show that many key developmental control factors are expressed in a temporal and spatial manner in the human VM essentially corresponding to what has been observed in the mouse."
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 Development
||Rhinencephalon, Amygdala, hippocampus, cerebrum (cortex), hypothalamus, pituitary | Basal Ganglia, lateral ventricles
||epithalamus, thalamus, Subthalamus, pineal, posterior commissure, pretectum, third ventricle
||tectum, Cerebral peduncle, cerebral aqueduct, pons
||medulla oblongata, isthmus
|spinal cord, pyramidal decussation, central canal
Genes differentially expressed in the Mouse Posterior Midbrain
In situ hybridizations on E15 brains from wild-type mouse embryos with specific cDNA probes of the transcription factors Pitx2, Mef2c, Bhlhb4 and Pou4f3.
- Top - lateral view.
- Middle - dorsal view.
- Bottom - ventral view.
- ↑ Watson C, Bartholomaeus C & Puelles L. (2019). Time for Radical Changes in Brain Stem Nomenclature-Applying the Lessons From Developmental Gene Patterns. Front Neuroanat , 13, 10. PMID: 30809133 DOI.
- ↑ Takahashi M & Osumi N. (2008). Expression study of cadherin7 and cadherin20 in the embryonic and adult rat central nervous system. BMC Dev. Biol. , 8, 87. PMID: 18801203 DOI.
- ↑ Ohuchi H, Fukui H, Matsuyo A, Tomonari S, Tanaka M, Arai H, Noji S & Aoki J. (2010). Autotaxin controls caudal diencephalon-mesencephalon development in the chick. Dev. Dyn. , 239, 2647-58. PMID: 20737506 DOI.
- ↑ Sakurai Y, Kurokawa D, Kiyonari H, Kajikawa E, Suda Y & Aizawa S. (2010). Otx2 and Otx1 protect diencephalon and mesencephalon from caudalization into metencephalon during early brain regionalization. Dev. Biol. , 347, 392-403. PMID: 20816794 DOI.
- ↑ Nelander J, Hebsgaard JB & Parmar M. (2009). Organization of the human embryonic ventral mesencephalon. Gene Expr. Patterns , 9, 555-61. PMID: 19825428 DOI.
- ↑ Hesse K, Vaupel K, Kurt S, Buettner R, Kirfel J & Moser M. (2011). AP-2δ is a crucial transcriptional regulator of the posterior midbrain. PLoS ONE , 6, e23483. PMID: 21858141 DOI.
Greene ND & Copp AJ. (2009). Development of the vertebrate central nervous system: formation of the neural tube. Prenat. Diagn. , 29, 303-11. PMID: 19206138 DOI.
Wassef M & Joyner AL. (1997). Early mesencephalon/metencephalon patterning and development of the cerebellum. Perspect Dev Neurobiol , 5, 3-16. PMID: 9509514
Yin M, Liu S, Yin Y, Li S, Li Z, Wu X, Zhang B, Ang SL, Ding Y & Zhou J. (2009). Ventral mesencephalon-enriched genes that regulate the development of dopaminergic neurons in vivo. J. Neurosci. , 29, 5170-82. PMID: 19386913 DOI.
Shim S, Kim Y, Shin J, Kim J & Park S. (2007). Regulation of EphA8 gene expression by TALE homeobox transcription factors during development of the mesencephalon. Mol. Cell. Biol. , 27, 1614-30. PMID: 17178831 DOI.
Matsunaga E, Katahira T & Nakamura H. (2002). Role of Lmx1b and Wnt1 in mesencephalon and metencephalon development. Development , 129, 5269-77. PMID: 12399317
Park M, Kitahama K, Geffard M & Maeda T. (2000). Postnatal development of the dopaminergic neurons in the rat mesencephalon. Brain Dev. , 22 Suppl 1, S38-44. PMID: 10984659
Tsukahara M, Suemori H, Noguchi S, Ji ZS & Tsunoo H. (2000). Novel nucleolar protein, midnolin, is expressed in the mesencephalon during mouse development. Gene , 254, 45-55. PMID: 10974535
Bally-Cuif L, Alvarado-Mallart RM, Darnell DK & Wassef M. (1992). Relationship between Wnt-1 and En-2 expression domains during early development of normal and ectopic met-mesencephalon. Development , 115, 999-1009. PMID: 1360404
Search Pubmed: Mesencephalon Embryology | Mesencephalon Development | Mesencephalon
- 3DMRI - Three-dimensional magnetic resonance imaging. A new technique that allows 3D analysis of embryonic structures. (More? Magnetic Resonance Imaging)
- 3rd ventricle - a fluid-filled space formed from neural tube lumen, located within the diencephalon (from the primary vesicle prosencephalon, forebrain).
- 4th ventricle - a fluid-filled space formed from neural tube lumen, located within the rhombencephalon (from the primary vesicle, hindbrain).
- adenohypophysis - (anterior pituitary) = 3 parts pars distalis, pars intermedia, pars tuberalis.
- afferent - refers to the direction of conduction from the periphery toward the central nervous system. Efferent is in the opposite direction.
- alar plate - embryonic dorsolateral region of the neural tube forming at spinal cord level dorsal horns (afferent) and brain level different structures.
- anlage - (German = primordium) structure or cells that will form a future adult structure.
- arachnoid mater - (G.) spider web-like used in reference to the middle layer of the brain meninges.
- astrocytes - cells named by their "star-like" branching appearance, are the most abundant glial cells in the brain, important for the blood-brain barrier.
- basal ganglia - (basal nuclei) neural structure derived from the secondary vesicle telencephalon (endbrain) structure from the earlier primary vesicle prosencephalon (forebrain).
- basal plate - embryonic ventrolateral region of the neural tube forming at spinal cord level ventral horns (efferent) and brain level different structures.
- brachial plexus - mixed spinal nerves innervating the upper limb form a complex meshwork (crossing).
- brain - general term for the central nervous system formed from 3 primary vesicles.
- buccopharyngeal membrane - (oral membrane) at cranial (mouth) end of gastrointestinal tract (GIT) where surface ectoderm and GIT endoderm meet. (see also cloacal membrane).
- cauda equina - (horse's tail) caudal extension of the mature spinal cord.
- central canal - lumen, cavity of neural tube within the spinal cord. Space is continuous with ventricular system of the brain.
- central cerebral sulcus - (central fissure, fissure of Rolando, Rolandic fissure) fold in the cerebral cortex associated with the sensorimotor cortex.
- cerebral aqueduct - ventricular cavity within the mesencephalon.
- cervical flexure - most caudal brain flexure (of 3) between spinal cord and rhompencephalon.
- choroid plexus - specialized vascular plexus responsible for secreting ventricular fluid that with further additions becomes cerebrospinal fluid (CSF).
- cloacal membrane - at caudal (anal) end of gastrointestinal tract (GIT) where surface ectoderm and GIT endoderm meet forms the openings for GIT, urinary, reproductive tracts. (see also buccopharyngeal membrane).
- connectome - term describing the detailed map of neural connections in the central nervous system.
- cortex - - CNS structure derived from the secondary vesicle telencephalon (endbrain) from the earlier primary vesicle prosencephalon (forebrain).
- cortical plate - outer neural tube region which post-mitotic neuroblasts migrate too along radial glia to form adult cortical layers.
- cranial flexure - (=midbrain flexure) most cranial brain flexure (of 3) between mesencephalon and prosencephalon.
- diencephalon - the caudal portion of forebrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). (cavity- 3rd ventricle) Forms the thalmus and other nuclei in the adult brain. (sc-My-Met-Mes-Di-Tel)
- dorsal root ganglia - (spinal ganglia) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord.
- dura mater- "tough" (Latin, mater = mother) used in reference to the tough outer layer of the brain meninges.
- efferent - refers to the direction of conduction from the central nervous system toward the periphery. Afferent is in the opposite direction.
- ependyma - epithelia of remnant cells after neurons and glia have been generated and left the ventricular zone.
- floorplate - early forming thin region of neural tube closest to the notochord.
- ganglia - (pl. of ganglion) specialized neural cluster within either the CNS or PNS.
- glia - supporting, non-neuronal cells of the nervous system. Generated from the same neuroepithelial stem cells that form neurons in ventricular zone of neural tube. Form astrocytes, oligodendrocytes.
- grey matter - neural regions containing cell bodies (somas) of neurons. In the brain it is the outer layer, in the spinal cord it is inner layer. (see white matter white matter).
- growth factor - usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg SHH).
- HOX - (homeobox) family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.
- hydrocephalus - abnormality as the result of an imbalance between the rate at which the CSF is being formed and the rate at which the CSF is passing through the arachnoidal villi back into the blood (hydrocephalus rate is a function of the degree of imbalance in these two). Very small imbalance exhibit subtle, if any, symptoms. Large imbalances will have rapidly evolving symptoms of unmistakable import.
- isthmus- (G. narrow passage).
- lamina terminalis - anterior region of brain where cranial neuropore closes.
- lumbar plexus - mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).
- mantle layer - layer of cells generated by first neuroblasts migrating from the ventricular zone of the neural tube. Layers are rearranged during development of the brain and spinal cord. (Ven-Man-Mar-CP)
- marginal zone - layer of processes from neuroblasts in mantle layer. (Ven-Man-Mar-CP)
- mater - (Latin, mater = mother) used in relation to the 3 layers of the meninges.
- meninges - mesenchyme surrounding neural tube forms 3 layer (Dura-, pia-, arachnoid- mater) connective tissue sheath of nervous system. (D-P-A-cns)
- mesencephalon - (midbrain), the middle portion of the 3 primary vesicle brain (week 4). (sc-R-M-P)
- metencephalon - the cranial portion of hindbrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). Forms the pons and cerebellum in the adult brain. (sc-My-Met-Mes-Di-Tel)
- microglia - CNS innate immune cells that have a macrophage function, derive from yolk sac progenitor cells migrating into the CNS. microglia
- myelencephalon - the caudal portion of hindbrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). Forms the medulla in the adult brain. (sc-My-Met-Mes-Di-Tel)
- neural tube - neural plate region of ectoderm pinched off to form hollow ectodermal tube above notochord in mesoderm.
- neural tube defect - (NTD) any developmental abnormality that affects neural tube development. Commonly failure of neural tube closure.
- neuroblast - undifferentiated neuron found in ventricular layer of neural tube.
- neurohypophysis - (posterior pituitary; pas nervosa)
- neuromere - (prosomere) the model units for segmental brain development regions based upon a series of neural tube transverse subunits.
- neuron - The cellur "unit" of the nervous system, transmitting signals between neurons and other cells. The post-mitotic cells generated from neuroepithelial stem cells (neuroblasts) in ventricular zone of neural tube.
- neuropore - opening at either end of neural tube cranial (rostral, anterior) neuropore closes (day 25) about 2 days before caudal (posterior) that closes at somite level 32 to 34. Neural Tube Defects (NTDs) can be due to failure of these two neuropores to close.
- notochord - rod of cells lying in mesoderm layer ventral to the neural tube, induces neural tube and secretes sonic hedgehog which "ventralizes" the neural tube.
- olfactory bulb - (cranial nerve I, CN I) bipolar neurons from nasal epithelium project axons through cribiform palate into olfactory bulb of the brain associated with smell.
- optic nerve - (cranial nerve II, CN II) retinal ganglion neurons project from the retina as a tract into the brain (at the level of the diencephalon) associated with vision.
- optic vesicle - diencephalon region of neural tube outgrowth that forms the primordia of the retina associated with vision.
- opercularization - during fetal development of the sensorimotor cortex, the insula (located deep within the lateral sulcus) begins to invaginate from the surface of the immature cerebrum, until at term, the opercula completely cover the insula.
- otocyst - (otic vesicle) sensory placode that sinks into mesoderm to form spherical vesicle (stage 13/14 embryo) that will form components of the inner ear associated with hearing.
- pharyngeal arch - (branchial arch, Gk. gill) form the main structures of the head and neck. Humans have 5 arches appearing in week 4 that form 4 external swellings, each arch has a pouch, membrane and cleft.
- pharynx - uppermost end of GIT, beginning at the buccopharyngeal membrane and at the level of the pharyngeal arches.
- pia mater - (G.) (L. pius = soft, faithful + mater = mother) delicate vascular membrane which adheres to surface of brain and spinal cord, faithfully following their contours, the inner layer of the brain meninges.
- placode - specialized regions of ectoderm which form components of the sensory apparatus.
- pontine flexure - middle brain flexure (of 3) between cervical and cranial flexure in opposite direction, also generates thin roof of rhombencephalon and divides it into myelencephalon and metencephalon. ( sc-^V^ )
- posterior insula - during sensorimotor cortex development this region is composed of the anterior and posterior long insular gyri and the postcentral insular sulcus, which separates them.
- prosencephalon - (forebrain), the most cranial portion of the 3 primary vesicle brain (week 4). (sc-R-M-P)
- prosomere - (neuromere) a model for segmental brain development based upon a series of neural tube transverse subunits. PMID 12948657
- Rathke's pouch - a portion of the roof of the pharynx pushes upward towards the floor of the brain forming the anterior pituitary (adenohypophysis, pars distalis, pars tuberalis pars intermedia). Where it meets a portion of the brain pushing downward forming the posterior pituitary (neurohypophysis, pars nervosa). Rathke's pouch eventually looses its connection with the pharynx.
- rhombencephalon - (hindbrain), the most caudal portion of the 3 primary vesicle brain (week 4). (sc-R-M-P)
- rhombic lip - metencephalon posterior part extending from the roof of the fourth ventricle to dorsal neuroepithelial cells that contributes to the cerebellum.
- roofplate - early forming thin region of neural tube closest to the overlying ectoderm.
- spinal cord - caudal end of neural tube that does not contribute to brain. Note: the process of secondary neuralation contributes the caudal end of the spinal cord.
- spinal ganglia - (dorsal root ganglia, drg) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord.
- spinal nerve - mixed nerve (motor and sensory) arising as latera pairs at each vertebral segmental level.
- sonic hedgehog - (shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons.
- sulcus - (L. furrow) groove.
- sulcus limitans - longitudinal lateral groove in neural tube approx. midway between roofplate and floorplate. Groove divides alar (dorsal) and basal (ventral) plate regions.
- telencephalon - the cranial portion of forebrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). (cavity- lateral ventricles and some of 3rd ventricle) Forms the cerebral hemispheres in the adult brain. (sc-My-Met-Mes-Di-Tel)
- thalamus - (G. thalamos= bedchamber) cns nucleus, lateral to 3rd ventricle, paired (pl thalami).
- thyroid hormone - hormone required for brain development. T3 (3,5,3′-triiodothyronine) binding to nuclear receptors then act as a transcription factor in both neurons and glial cells. iodine deficiency
- transcription factor - a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2)
- trigeminal ganglion - (cranial nerve V, CN V) first arch ganglion, very large and has 3 portions.
- vagal ganglion - (cranial nerve X, CN X) fourth and sixth arch ganglion, innervates the viscera and heart.
- ventricles - the fluid-filled interconnected cavity system with the brain. Fluid (cerebrospinal fluid, CSF) is generated by the specialized vascular network, the choroid plexus. The ventricles are directly connected to the spinal canal (within the spinal cord).
- ventricular zone - Neuroepithelial cell layer of neural tube closest to lumen. Neuroepithelial cells generate neurons, glia and ependymal cells. (Ven-Man-Mar-CP)
- vestibulocochlear nerve - (cranial nerve VIII, CN VIII, also called statoacoustic)
- white matter - - neural regions containing processes (axons) of neurons. In the brain it is the inner layer, in the spinal cord it is outer layer. (see grey matter).
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Cite this page: Hill, M.A. (2020, June 5) Embryology Neural - Mesencephalon Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Neural_-_Mesencephalon_Development
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