Neural tube formation Flashcards
LO
- Explain the mechanisms of neural plate induction
- Describe the steps of primary neurulation
- Explain the molecular mechanisms of hinge point formation, neural tube closure, fusion and separation during primary neurulation
- Explain where and how the neural crest originates
- Explain the molecular and cellular mechanisms of neural crest cell migration
What are the three major derivative of the ectoderm germ layer?
- Surface ectoderm (primarily epidermis)
- Neural tube (brain and spinal cord)
- Neural crest (peripheral neurons, pigment, facial cartilage)- pluripotent stem cells
What is the ‘default rate’ of the ectoderm to become?
The neural tissue
Name 3 proteins that bind to BMPs and what is their role?
Chordin, Noggin and Follistatin
bind directly to BMPs (Bone Morphogenetic Proteins) to block their interaction with BMP receptors- mesodermal cells release these and are antagonists to BMP signaling pathway
Where is Chordin, Noggin and Follistatin expressed?
In the dorsal mesoderm
Neural ectoderm neural induction
Implicated in neural induction (mechanism: inhibition of TGFβ (transforming growth factor beta) signalling in the ectoderm)
What has BMP4 signalling been identified in?
BMP4 signalling has been identified in ectoderm cells differentiating into epidermis skin cells
The role of Chordin, noggin and follistatin is to inhibit BMP signalling and induce neural plate formation
BMP ligands are members of what superfamily?
TGF-beta
What do BMP ligands bind to?
Ligand binds to a TGF-β type II receptor (serine/threonine receptor kinase)
Tell me about BMP signalling
- Member of TGF-β signalling superfamily
- Ligand binds to a TGF-β type II receptor (serine/threonine receptor kinase)
- Forms dimer with type 1 receptor and the kinase phosphorylates Type 1 receptor
- Downstream phosphorylation of cytoplasmic SMAD proteins follows
- SMAD complex enters nucleus and regulates transcription of target genes
Neural tube formation in an amphibian embryo
Tell me about the control of neural specification by levels of BMPs
(A) Control embryo with neural folds stained for the expression of the neural gene Sox2
(B) Lack of neural tube and Sox2 expression in an embryo treated with the morpholinos against three BMP inhibitors (chordin, noggin, follistatin)
(C) The neural tube, visualized by Sox2 staining, is greatly enlarged in embryos treated with antisense morpholinos that destroy BMPs 2, 4, and 7
(D) Complete transformation of the entire ectoderm into neural ectoderm (and loss of the dorsal-ventral axis) by inactivation of BMPs 2, 4, and 7
The soluble protein Noggin dorsalises the amphibian embryo
Localization of Noggin mRNA within organizer and subsequently notochord (this example is from the frog)
(B) Localization of noggin mRNA in the organizer tissue, shown by in situ hybridization
At gastrulation (i), noggin mRNA (dark areas) accumulates in the dorsal marginal zone.
When cells involute (ii), noggin mRNA is seen in the dorsal blastopore lip
During convergent extension (iii), noggin is expressed in the precursors of the notochord, prechordal plate, and pharyngeal endoderm,
Which (iv) extend beneath the ectoderm in the center of the embryo
Label this cross section of late neurula
Primary neurulation in the chick embryo (part 1)
- The neurulating chick embryo (dorsal view) at about 24 hours
- The cephalic (head) region has undergone neurulation
- The caudal (tail) region is still undergoing gastrulation
How can cells of the neural plate be distinguished?
(A, 1a) Cells of the neural plate can be distinguished as elongated cells in the dorsal region of the ectoderm
Where does folding in the neural tube begin and where does it move towards?
(B, 1b) Folding begins as the medial hinge point (MHP) cells anchor to the notochord and change their shape while the presumptive epidermal cells move toward the dorsal midline
The neural folds are elevated as the presumptive epidermis continues to move toward what?
(C, 2a) The neural folds are elevated as the presumptive epidermis continues to move toward the dorsal midline. Asymmetric constriction of actin on the apical side changes cell shapes to promote MHP bending (B, C, 2b)
Where does convergence of the neural folds occur at?
(D, 3a) Convergence of the neural folds occurs as the cells at the dorsolateral hinge point (DLHP) become wedge-shaped and the epidermal cells push toward the center. (D, 3b) Similar apical constriction occurs at the DLHP
Tell me the final step of primary neurulation in the chick embryo and where the neural folds are brought into contact with?
(E, 4) The neural folds are brought into contact with one another. The neural crest cells disperse, leaving the neural tube separate from the epidermis (notochord remains in these last steps and helps formation of neural tube and also helps release key molecules which helps the process)
Primary neurulation in the chick embryo (part 2)
Neurulation in a mouse embryo
Live imaging of a 15-somite stage embryo using a transgenic CAG:Venusmyr mouse to visualize all cell membranes
Optical dorsoventral (cross) sections show DLHP formation (curving of white line on left fold) to the point of near closure (decreasing size of double arrow)
What does activated BMP signalling lead to?
Neural tube defects
What does a loss in noggin result in?
failure of neural tube closure
Tell me the following about noggin: Affiliated with, uniquely expressed in, positively regulates, binds to what and the effect it has
Loss of Noggin results in failure of neural tube closure
- Affiliated with the dorsal blastopore lip during gastrulation
- Uniquely expressed in the neural folds
- Positively regulates neural tube closure
- Binds directly to and inhibits BMP4
Where are the following expressed:
- BMPs
- Noggin
- Shh
- BMPs are expressed by the surface ectoderm (green)
- Noggin is expressed in the dorsal neural folds (blue)
- Shh (sonic hedgehog) is expressed ventrally in the notochord and floor plate
The regulation of the hinge points revolves around BMP and acts as an antagonist to what?
Both DLHP and MHP formation
Tell me about the regulation of hinge points around BMP…
- Shh is required for the specification of floor plate, while additional signals from the notochord induce MHP (medial hinge point) morphology
- Noggin directly inhibits BMP ligands, thus alleviating BMP repression of the hinge points.
- The DLHPs, however, only form at the correct size and dorsal-ventral position, which is based on Noggin’s distance from inhibitory Shh gradients ascending from the floor plate.
What cells experience apical constriction?
Apical constriction occurs only in those cells experiencing low enough concentrations of both BMP (MHP and DLHP) and Shh (DLHP) morphogens
Name an inhibitor of noggin
Shh
If theres no Shh present, what can noggin do?
No Shh, noggin can lead to more DLHP (dorsal lateral hinge point) which can impair the primary neurulation process. So need to make sure its localized at this point
Tell me the effects caused by either low or excessive BMP signalling
Dosage is important: High levels of BMP signaling inhibit MHP formation while low levels promote excessive folding at the midline
During neural tube closure at the midbrain region, what do non-neural ectodermal cells establish?
What can Larval ciona be used as a model to study?
Neural tube formation
What direction does fusion of the neural folds zippers in?
A posterior to anterior direction
What is the essential roles of differential adhesion regulation?
- Cadherin family of CAMs
- facilitate homophilic binding
- Keep cells expressing cadherin type and amount adhered together
What does differential E- and N-cadherin expression pattern allow for during neurulation?
Name two disorders that can come about for defects in neural tube closure in the mammalian embryo
Exencephaly
Anencephaly
Whats exencephaly?
Whats Anencephaly?
Early brain development and formation of the first brain chambers
Summary
- Neural plate (thickened region in the ectoderm) forms (induced by underlying mesoderm)
- Bending of the neural plate begins at the medial hinge point (notochord-dependent)
- Medial push of epidermal ectoderm and cell shape changes at the dorsolateral hinge points cause convergence of the elevated neural folds
- Neural folds give rise to neural crest cells, which disperse, and the neural tube separates from the epidermis
- The neural tube develops three primary vesicles, and further into five secondary vesicles, from which the brain develops
