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The developing neural tube is patterned along which axis?
Anterior-Posterior axis (AP)
What are the 4 regions of the pipe structure?
- Spinal cord
What are the 5 morphological structures of the brain? Where are they located?
- Telencephalon: forebrain
- Diencephalon: forebrain
- Mesencephalon: midbrain
- Metencephalon: hindbrain
- Myelencephalon: hindbrain
What regions are formed from the telencephalon?
- Olfactory bulb
- Cerebral cortex
- Basal ganglia
What regions are formed from the diencephalon?
What regions are formed from the mesencephalon?
What regions are formed from the metencephalon?
What regions are formed from the myelencephalon?
When is the layout of the brain specified?
Early in development
There is a clear separation between which two regions?
Brain and spinal cord
What portions are included in the three-vesicle stage?
- Caudal neural tube
What portions are included in the five-vesicle stage?
- Telencephalon; Lateral ventricle
- Diencephalon; Third ventricle
- Mesencephalon; Cerebral aqueduct
- Metencephalon; Fourth ventricle
- Myelencephalon; Fourth ventricle?
- Spinal cord; Central canal
- Neural retina and lens
What is wnt?
Secreted molecule in the neural plate
What is wnts role?
Signaling is important for patterning the neural plate along the anterior-posterior axis
At what stage does wnt signaling happen?
Very early stage
There is a clear distinction between which two regions of the brain?
- Midbrain and hindbrain
Which region is there high wnt secretion? Low secretion?
- High: hindbrain (posterior)
- Low: forebrain and midbrain (anterior)
What are the segments of the hindbrain called?
What are rhombomeres?
- Segments of the hindbrain
- Literally, bumps. Series of bumps.
When are specializations in the hindbrain shown?
Later in development
What do rhombomeres do?
- Give rise to various structures
- Express different genes during development
Whats contained in the rhombomeres?
The soma (cell body) of the motor neurons of different cranial nerves
What are homeotic genes?
Genes which regulate the development of anatomical structures in various organisms
In what species were homeotic genes originally identified?
Drosophila (fruit fly)
What are responsible for establishing body plan along AP axis?
Transcription (tx) factors in homeobox genes
What are transcription factors in homeobox genes responsible for?
Establishing body plan along AP axis
Where are homebox genes clustered?
In the genome/chromosome
What does the order of the cluster of transcription factors correlate with?
Order of importance of expression along AP axis
Which genes in vertebrates and humans are related to fly homeobox genes?
How are hox genes expressed?
In overlapping domains along the AP axis of the developing brain and spinal cord
Where are the hox genes clustered?
In the genome
Hox genes are implicated in determining the identity of what?
Rhombomere fate and identity is determined by what?
The boundaries of hox gene expression coincide with what?
- Genes related by duplication within a genome
- Evolve new functions, even if they are related to the original one
- Expression is correlated with order and structure
Anterior of hox genes coincide with what?
Anterior of rhombomere
Which motor neurons occupy the rhombomeres?
- Trigeminal Nerve (r2 and r3)
- Facial Nerve (r4)
- Abducens Nerve (r5)
- Glossopharyngeal Nerve (r7)
- Vagus Nerve (r8)
What happens when you genetically delete Hoxa1(-/-)?
- Decrease in the number of rhombomeres (about 5 vs. 7 rhombomeres)
- Expansion of r3; loss/reduction of r4 and r5
- Loss of abducens; reduction of facial nerves
What regulates Hox expression?
What happens with retinoic acid as you go from r1 to r7?
Production and secretion of retinoic acid increases
Where is retinoic acid produced at the highest level?
Posterior of hox genes and hindbrain (r7)
What does the sensitivity to retinoic acid mean?
- Most sensitive can be activated with lowest RA concentration
- Least sensitive with higher concentration
Which part of the gene and hind brain is most sensitive to retinoic acid? Least?
- Most- anterior
- Least- posterior
Hindbrain segmentation involves what?
Hierarchical relationship of genes
What happens when you block retinoic acid?
- Size of r1-4 increases
- r4 increases most
- r5-8 disappears
Why does r5-8 disappear when retinoic acid is blocked?
- Theyre the least sensitive so they need a lot of retinoic acid
- But since theres no RA, they try to expand but disappear
Spinal cord is specialized along which axis?
Dorsal-Ventral axis (DV)
What happens in the ganglion of the dorsal root of the spinal cord?
Sensory cells send axons in
What happens in the ventral root of the spinal cord?
Motor neuron cell bodies send axons out
What is between the sensory neurons and the motor neurons?
What is important for induction?
When does specialization start?
At the tube
Where are most motor neurons located?
Closer to the floor plate (ventral)
What are the two specializations?
Floor and roof plate
In an abnormal place or position
What happens when you remove or transplant ectopic notochord?
Notochord induces ventral cell fates
What happens when notochord is removed?
No floor plate or motor neurons
What happens when notochord is transplanted on the side somewhere?
See 2 floor plates and 2 places for motor neurons
What does the transplant/removal of the notochord show?
Notochord is necessary and sufficient for induction of motor neuron cell fate
What happens when you culture intermediate plate explants on floor plate (or notochord) explants?
Cells adopt ventral cell fates (motor neurons)
What happens when intermediate plate explants are cultured with conditioned medium from floor plate?
A diffusible factor is the inducer
What does a diffusible factor from floor plate or notochord do?
Induces motor neurons
What is the signal released by the notochord?
Sonic Hedgehog (SHH)
What is Sonic Hedgehog?
- SHH = morphogen
- Secreted protein expressed early in the floor plate and notochord
- Signal that induces ventral (MN) fate
What does SHH signaling require?
The smoothened receptor
What effect does the patch protein normally have on the smoothened?
Patched inhibits smoothened
What effect does Hedgehog have on the patch protein?
HH binds to patch to inhibit inhibition
Where in the tube (spinal cord?) is there a high level of BMP?
In the roof plate
Why is there a high level of BMP dorsally?
BMP signaling in the ectoderm so when it creates the neural tube, the top of the tube where its pinched together is gonna have the BMP signaling
What kind of gradient does BMP have?
High dorsal, low ventral gradient
What happens when you add an ectopic notochord dorsally?
- Ventralization of the spinal cord (additional floor plate and motor neurons dorsally)
- Extinguished BMP expression
What was the point of the dorsal induction experiment of dorsally adding an ectopic notochord?
Suggests that BMP is needed for dorsalization, but doesnt prove it
What was the complementary experiment for dorsal induction?
Removal of the notochord
What was the result of removing the notochord?
- Lack of ventral phenotype (no floor plate or motor neurons)
- BMP expressed everywhere
What was the point of the dorsal induction experiment of removing the notochord?
Suggests that BMP inhibits ventralization, but doesnt prove it
What are explant co-culturing experiments?
Culturing intermediate plate (IP) explants on floor plate (FP) explants
What do explant co-culturing experiments show?
- IP cells adopt ventral cell fates (MN) in absence of BMP
- If there is BMP in the medium, then BMP inhibits ventralization
- This shows the role of BMP signaling in repressing ventral fates
What ultimately determines cell fates in the spinal cord?
Opposing BMP and SHH signaling along DV axis
What are the effects of BMP on the cell fates?
- Inhibits ventral
- Induces dorsal
What are the effects of SHH on the cell fates?
- Induces ventral
- Inhibits dorsal
What is the effect of the two gradients working in opposition?
What do the different cellular responses, according to position of the cell in the concentration gradient of a morphogen (shh or bmp), result in?
Discrete differences in cell fate along the gradient due to the graded concentration of morphogen
What do the SHH levels determine?
What does the particular fate of the different cells in the ventral neural tube depend on?
- The amount of SHH that they are exposed to
- Their location on the DV axis
What is the fate of the cells in the ventral neural tube that are exposed to LOW concentration of SHH?
What is the fate of the cells in the ventral neural tube that are exposed to MEDIUM concentration of SHH?
What is the fate of the cells in the ventral neural tube that are exposed to HIGH concentration of SHH?
Floor plate cells
What does the expression of homeodomain transcription factors allow for?
A readout of SHH gradient in ventral spinal cord
What does the repression of class I homeodomain protein expression by SHH signaling do?
Sets discrete boundaries
What are the class I homeodomain transcription factors?
What are the class II homeodomain transcription factors?
Which transcription factors mutually repress each other?
- Pax6 and Nkx2.2
- Dbx2 and Nkx6.1
The combination of what determines cell fate?
Combo of homeodomain proteins/transcription factors expressed
What determines which transcription factor is expressed?
The level of SHH that the cell sees
What codes for ventral spinal cord cell fates?