Ventralisation of the NS Flashcards
What happens after neural plate (neuroepithelium) is induced
It rolls up into the neural tube. This transforms the medio-lateral axis into the dorso-ventral axis.
Lateral edges fuse to become dorsal part of neural tube (remember ‘dorsal’ and ‘ventral’ are all relative terms). The neural tube ‘pinches off’ from the overlying surface ectoderm.
At same time that neural plate/early neural tube are forming,
the axial mesoderm (notochord and prechordal mesoderm) forms, and comes to lie just below the ventral midline of the neural tube
What do neurons develop around the midline, throughout the entire dorso-ventral (D-V) axis
Neurons develop with bilateral symmetry
Where are the notochord and floor plate located and what do they secrete?
Notochord and floor plate are located at the ventral midline: they secrete another morphogen (Shh)
How can you test notochord and floor plate are located on ventral midline?
Test by grafting a donor notochord or floor plate to an ‘ectopic’ position in a host embryo.
Ask if ectopic floor plate/ and ectopic ventral neurons are induced
Ectopic floor plate and ventral neurons (such as motor neurons) induced after graft of notochord or floor plate
Expression of Shh and Shh signalling
Shh comes from the notochord and later floor plate.
Shh signalling induces expression of transcription factors in progenitor cells. These transcription factors confer ‘ventral’ neural tube identities, so the progenitors will ultimately give rise to cells that differentiate into ventral neurons
What was induced after implantation of Shh-soaked bead? and what does it mimic
Ectopic floor plate and ventral neurons (such as motor neurons) induced.
A bead soaked in purified SHh protein can mimic the effect of the notochord/floor plate
What happens after notochord has formed?
It begins to make a key secreted signal - termed Shh. Shh diffuses through the spinal cord, establishing a concentration gradient. It acts as a morphogen - inducing distinct patterns of gene transcription at particular concentrations
Highest concentrations of Shh cause
neural cells to differentiate into ‘floor plate’ cells. These occupy the ventral midline of the neural tube and themselves come to turn on SHh
How do we know Shh induces particular Tfs?
because we can use in itu hybridisation methods or immunohistochemistry to detect these.
How are progenitor domains (made up of proliferating bands of cells) established?
Established through opposing action of BMPs/Wnts (dorsallly) and Shh (ventrally)
Over time, these differentiate and migrate laterally (radially) to form the defined neurons of the spinal cord (circles, panel 2).
They then extend axons
Shh pathway in unstimulated cells
In unstimulated cells, the activity of the transmembrane protein Smo is suppressed by the Hh receptor Ptc and the majority of the Gli transcription factors are present in their repressive (R) form
Shh pathway in stimulated cells
In stimulated cells, binding of Hh to Ptc activates Smo, which in turn shifts the Gli balance in favor of the activator (A) forms, resulting in the transcription of Hh target genes
Multiple dysmorphology in Shh-/- mouse
No ventralisation of neural tube Abnormal limbs/digits
Holoprosencephaly Lack of pituitary
Cyclopia
Holoprosencephaly
A failure of the ventral forebrain to form - (and failure of pituituary, cyclopia, general problems withi midline of face) - found to be due to mutations in Shh/Shh signaling components.
What happens when Shh coming from ventral cell groups
It intersects with the earler-established A-P domain of the neural tube.
This effectively creates a ‘Cartesion grid’ of information - cells respond by changing fate in accordance with their position in the grid.
Hence, different types of neurons differentiate at the same D-V position along different parts of the A-P axis (B) - eg in the forebrain, SHh induces hypothalamic neurons (red dots), in the midbrain it induces dopaminergic neurons (purple dots), in the hindbrain, serotonergic neurons (blue) and motor neurons elsewhere (manily spinal cord - olive green)
What can we conclude?
Mechanisms through which BMP/Wnt/Shh gradients converted to a GliA-GliR gradient, and the induction of transcription factors that then act cell-autonomoulsly to determine progenitor identity and ultimate fate
