What is the function of each neural progenitor domains? 

Pax7

Pax 6

Olig2

Nkx2.2

FoxA2

Pax 7 = involved in neural crest development

Pax6 = involved in eye and cerebral hemisphere development

Olig2 = linked to downs' syndrome

FoxA2 = linked to diabetes. 

Even though diverse organisms use the same or similar 

genes for development, phenotypic diversity is not due to 

just slightly different patterns of gene expression. 

Timing and amount of secreted proteins and transcription 

factors can influence neural tube development dramatically 

white matter is white because they are myelinated. It contains lots of glial cells wrapped with myelin. This speeds conduction across axon (~470km/hr = speed of transmission)

Grey matter (central brain) not myelinated. This is wher most of the cell bodies are located. cell bodies are not myelinated so they appear grey. 

- position of neural tube is relativ to mesodermal organizing centers (ex. notochord). 

- initially is a neural groove and then it turns to neural tube

- dorsal area is called neural crests. They are special types of neurons that do lots of things. 

- consists of undifferentiated neural progenitors. but, there are already signs of dorsal-ventral differentiation 

The dorsal half is the alar plate. Bottom half is the basal plate. There's a central opening called the centrl canal. This is very narrow because cord is taken up by neurons and cells and thus constricts the central canal. Mantle layer is where the grey bodies will develop. 

Ependymal layer:  mitotic nerve cells line the surface of what will be the central canal 

Mantle layer:   future grey matter (neuronal cell bodies)

Marginal layer:   future white matter (neuronal axons) 

sulcus limitans:   fissure separating (dorsal) alar plate (sensory cells) from (ventral) 

basal plate (motor cells)

Dorsal: sensory (alar plate in neural tube) 

Ventral: motor (basal plate in neural tube) 

Sensory neurons go to dorsal horn. 

Ventral half is the motor neurons going to muscles. Motor neurons activated directly by sensory neurons or via interneurons. 

Propiospinal : regulate multiple activities within the spinal cord. 

These experiments identified the notochord as an organizer: 

Notochord secretes a signal that triggers formation of neural tube & 

determines which part takes on ventral identity within the neural tube. 

If no ventral notochord, thus transplant an additional ventral part of the neural tube. One of these are GOF and other is LOF experiment. ****

B. LOF

C. GOF

Sonic Hedgehog (Shh)

Exposing tissues to different transcription factors. 

Sonic hedg: induce development of ventral neural tube just by presence of notochord. 

•  Explants of intermediate neural tube express characteristic transcription factors 

•  Notochord and explant separated in collagen gel: ventral transcription factors and 

choline acetyltransferase(chAT) expressed in differentiating α-motor neurons (chAT

necessary enzyme in formation acetylcholine, the motor neuron neurotransmitter). 

•  SHH protein is sufficientto induce expression of ventral portion of 

neural tube. Shhis a morphogen, which is a molecule that diffuses to form a 

concentration gradient that has differential effects on cells of the neural tube 

depending on its concentration. SHH remains important in the adult. It influences 

cell division of adult stem cells within the CNS. 

- its a secreted protein 

•  Drosophila homolog, hedgehog,originally cloned 

from stubby surface of mutant drosophila that 

looked like a “hedgehog” 

•  Shh(mammalian equivalent named after Sega 

video game) appears first in notochord, then in 

floorplate: 

notochord induces floorplate(which in turn 

becomes a signaling center, also expressing SHH)

SHH is being expressed in ventral notochord. ventral neural tube show more expression over time. 

The notochord is the source of SHH.  

•  a developmental disorder where the forebrain fails to completely develop 

into 2 bilaterally symmetrical hemispheres (i.e. failure to develop midline 

brain structures). 

•  Mild forms of the disorder may be characterized by a small head and 

defects in facial development (e.g. narrow spacing between eyes). 

•  More severe forms are often lethal and some have a cyclopia phenotype. 

•  Inappropriate expression of Shh, Pax2 and/or Pax6genes are suspected 

causes of HPE (but exact details of disorder not well understood). 

Eye do not become lateral. Theres only one. like a cyclone. 

Whats involved is Pax6/2 and SHH. Brain starts to divide into sections and then divide into ventrals. But in this case, they dont. They dont form bilateral features. Most of these are very lethal. Most children are still born. 

A gradient of Shh gene expression (thus SHH protein) determines cell fate in 

the ventral neural tube

•  Discrete and different neuronal populations arise from spatially separated 

progenitor domains 

• Cell fate is determined by the concentration of SHH at each dorsal-ventral position 

SHH gradient governs the expression of transcription factors 

•  Distinct domains are defined by expression of a characteristic combination of genes

TFactors are divided into Class1 and 2. 

They can suppress each other and turn off other genes. If have ventral TF and some in dorsal, they can suppress each other. 

TFactors are divided into Class1 and 2. 

They can suppress each other and turn off other genes. If have ventral TF and some in dorsal, they can suppress each other. 

•  In the absence of Shh, 

transmembranereceptor Patched 

(PTCH1) inhibits Smoothened (SMO, 

a G-coupled receptor protein) 

•  SHHbinds to PTCH1and alleviates inhibition of SMO 

• Signal is transduced to the nucleus by the GLIfamily of Zinc-finger 

transcription factors (GLi1, GLi2, GLi3). Activated GLIin the nucleus 

controls the transcription of hedgehog target genes. 

• PTCH1 has also been reported to repress transcription of hedgehog 

target genes through a mechanism independent of SMO.

LOF experiments: antibodies raised against SHH prevent differentiation of floor plate and motor neurons; Shh Knockout (KO) mutant mice have a similar phenotype 

[note: Shh also critical in dorsal-ventral patterning of the brain] However, other signaling molecules also confer ventral identity in the neural tube…

Note: Although Shh is required for development of MNs and several populations of ventral interneurons, competence for ventral specification is set up before Shhexpression. 

- function in dorsal-ventral patterning

-•  FGF2 strongly inhibits expression 

of Class I transcription factors: 

ventralizing(overall) 

•  RA promotes expression of Class I 

transcription factors: dorsalizing

•  RA and FGF2 originate from 

adjacent mesodermal tissue 

Hh= Hedgehog (Drosophilaequivalent of Shh) 

expressed in ventral part and then moves laterally. Things can have an effect and then disappear. Others will increase expression and then greater. Any pattern of expression will occur in the nervous system (NO SUCH THING AS BLACK AND WHITE)

RA is a dorsalizing feature. 

RALDH2 = retinalaldehyde dehydrogenase 2 is an enzyme that catalyzes synthesis of retinoic acid (RA) from retinal aldehyde 

- creates a gradient in the dorsal neural tube

(Like SHH) BMPs regulate transcription 

factor expression to govern dorsalventral fate: 

Dorsal genes are activated by BMPs 

Ventral genes are inhibited by BMPs 

Dorsal cell types require higher 

concentrations of BMPs 

antagonize one another to establish dorsal-ventral fate

• Adding BMPs with SHH prevents expression of ventral markers 

BMPs and RA induce dorsal fate in the neural tube and 

presence of Wnts also induces neural crest 

Neural crest arises from the most dorsal portion of the neural tube

The pattern of cell division (detected by BrdUincorporation in red) correlates with the pattern of Wnt expression and signaling: there is a dorsal-to-ventral gradient of proliferation (chick). The pattern of cell differentiation (visualized with neuron-specific 

markers in green) is inversely correlated with the pattern of Wnt expression and signaling: there is a dorsal to vetnral gradient for proliferation and an opposite ventral-to-dorsal differentiation gradient 

Note: BrdU(Bromodeoxyuridine) can substitute for thymidine and be incorporated into the newly synthesized DNA of dividing cells. Antibodies against BrdUcan then be used to detect replicating cells. N-tubulin is a marker of differentiated neurons

•  SHH expressed first in notochord, then 

later in floor plate cells 

•  RA and FGF are expressed in mesoderm 

•  BMP expressed first in ectoderm, then 

later in roof plate cells 

•  Wnts are expressed in roofplate cells 

(induced by BMPs) 

•  All of these regulate expression of regionspecific transcription factors to confer 

dorsal-ventral identity 

a transcription factor (sometimes called a sequence-specific DNA-binding factor or DNA-binding protein) is a protein that binds to specific DNA sequences, thereby 

controlling the flow (or transcription) of genetic information from DNA to messenger RNA (mRNA). Transcription factors perform alone or with other proteins in a complex, 

by either promoting (as an activator), or blocking (as a repressor) the recruitment of RNA polymerase (the enzyme that performs the transcription of genetic information from DNA to RNA) to the gene in question. 

Transcription factors always contain one or more DNA-binding domains, which attach to specific sequences of DNA (usually through a homeodomainsequence), adjacent to the genes they regulate. 

Additional proteins such as coactivators, chromatin remodelers, histone acetylases, deacetylases, kinases, and methylases, while also playing crucial roles in gene 

regulation, lack DNA-binding domains, and, therefore, are not classified as transcription factors and often referred to as Epigenetic factors. Epigenetics is the study of heritable changes in gene expression and the resulting cellular phenotype caused by mechanisms other than changes in DNA sequence. DNA methylation and histone modification are 2 such epigenetic mechanisms

RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific messenger RNA (mRNA). Two types of small ribonucleic acid (RNA) molecules – microRNA (miRNA) and small 

interfering RNA (siRNA) – are central to RNA interference. RNAs are the direct products of genes, and these small RNAs can bind to other specific messenger RNA 

(mRNA) molecules and either increase or decrease their activity, for example by preventing an mRNA from producing a protein. RNA interference has an important 

role in defending cells against parasitic nucleotide sequences – viruses and bacterial transposons – but also in directing development and general gene expression. 

RNAihas become a valuable research tool, both in cell culture and in living organisms, because synthetic double stranded RNA (dsRNA) introduced into cells 

can selectively and robustly induce suppression of specific genes of interest. RNAi may be used to systematically shut down each gene in a cell, which can help identify 

the components necessary for a particular cellular process (e.g. cell division). RNAi can also be used as a practical tool in biotechnology and medicine.