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BIOL 458
Lecture 3
43
Biology
Undergraduate 4
01/14/2014

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Term
Define Neural Induction
Definition
•  initial determination of neural tissue
Term
Define Early Patterning
Definition

•  transforming (determining) neural tube 

character 

(initial focus on rostrocaudal patterning) 

Term
The same gene or protein can have different actions, depending on what 4 characteristics?
Definition

•  cell location 

•  timing of expression 

•  amount of expression 

•  expression of complementary molecules 

Term
What is an organizer as defined by Spemann in 1921?
Definition

a piece of embryonic 

tissue that “creates an ‘organization field’of a certain 

[axial] orientation and extent …”,   

Term
The definition of an organizer embodies what?
Definition

embodies both induction and patterning, 

although these two effects can be generated by separate 

molecules: 

Term
The two effects of induction and patterning can be generated by which three separate molecules?
Definition

•  organizer cells change the fate of responding tissue 

•  generate (or transform) an‘organized’set of structures 

•  often via some secreted diffusible molecule(s) 

Term
What does the notochord organize?
Definition

organizes dorsal and 

ventral regions of developing spinal cord

- if you add notochord on the side, it will specify another notochord on that side. This is an example of a tissue specifying another tissue. 

Term
What does the developmental stage (time) or region of organizer tissue determine?
Definition

- determines whether inudced neural tissue is anterior (head) or posterior (tail) 

 

- The newly transplanted area can give rise to another secondary head or a secondary tail 

Term
What is the initial neural tissue like?
Definition

- the initial neural tissue becomes the neural tube which looks similar to all vertebrates. It first starts to close ner the head. Problems with the neural tubes are FATAL. 

 

Term
How does the neural tube close?
Definition

1. closure of the neural tube to form an actual tube does not occur all at once

2. begins approx. at the level of the fourth somite (future cervical cord region) around embryonic day 20 in humans. the lateral edges of the neural plate touch in the midline and join ogether. 

3. This continues both cranially (towards the head) and caudally (towards the tail). 

4. Openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. 

5. In human embryos, the cranial neuropore closes on ~25 days and caudal neuropores on ~ day 27. 

Term
What is Spina Bifida?
Definition

Failure of cranial and 

caudal neuropore 

closure results in 

conditions called 

anencephaly and 

spina bifida, 

respectively. 

•  Spina bifida is one of 

the more common 

birth defects with an 

incidence of 1 in 

a1000 births. 

Term
Serious spina bifida can be characterized by what?
Definition

can be characterized by a mylomeningocele, 

where unfused spinal vertebrae allow spinal cord and meninges 

to protrude. Loss of function at or below level of spina bifida can 

occur (similar to spinal cord injury). Prophylactic folic acid 

(vitamin B9) supplements can reduce incidence of spina bifida. 

Term
How is the brain vesicles differentiated?
Definition

1. anterior neural tube bulges into 3 primary vesicles which then differentiated into 5 secondary vesicles. 

 

2. neual tube will expand and create  chambers one of which the forebrain, midbrain and hindbrain. 

 

3. neurocoele becomes the cerebral ventricals. Later will see further separation

Term

What does the 

  metencephalon and mylencephalon become? 

Definition
pons, medulla
Term
What does the BMP inhibitors generate?
Definition

- rostral (anterior) 

- and neural tissue first 

Term
What happens to animal caps treated with BMP inhibitors?
Definition

 Animal caps treated with BMP 

inhibitors (e.g. Chordin, Noggin, 

Cerberus) form neural tissue which 

is rostral (brain-like) in character 

(expresses anterior genes) 

Term
what do chordin and noggin double KO mice lack?
Definition

Chordinand Noggin 

double KO mice lack 

rostral brain structures 

(anencephaly), but 

caudal neural 

structures are 

relatively normal 

(brainstem & spinal 

cord)

Term
What is the Nieuwkoop's activation?
Definition

The transformation model of neural induction

Ectoderm --> (signal 1 = activation, neuralizes and also speciies forebrain) --> Prospective forebrain --> (signal 2: transformaion (caudalizes)) --> midbrain --> hindbrain, spinal cord 

 

• Induction occurs in two steps: initial induction of forebrain, and 

then subsequent transformation of the rest of the neural tube. 

• Gradient represents either increasing strength of the transforming 

signal, or increasing time of exposure to this signal.

Term
What are the 3 classes of molecules that act as transformers?
Definition

1.  Retinoic acid (metabolite of vitamin A) 

2.  FGF (fibroblast growth factor)

3.  Wnt ("wnt" is a fusion of two terms, wgderived from Drosophila gene wingless (wg) 

and intderived from the proto-oncogene integration-1; the mammalian homolog of wg) 

Term
What is retinoic acid?
Definition

- invovled in determinin what is anterior, post, etc. Some of the mesodermal tisssues release retinoic acid. 

 

RA does not induce neural tissue 

but transforms anterior to 

posterior neural tube. 

 

RA come from segmented 

mesodermal tissue such as 

the notochord (notochord will 

become the intervertebral 

discs of the mammalian spinal 

column) 

Term
RA is expressed in gradients. Where is noggin and RA high in expression?
Definition

Noggin is a protein that has a role in neurulation by inhibiting BMP4 and 

also transforming early neural tube tissue into rostral brain structures. 

Note: expression is concentrated in rostral part of CNS (expression within 

skeleton underscores mesodermal origin of noggin).

 

 mouse carrying a retinoic acid-reporter gene. Note: concentrated 

expression within posterior (caudal) CNS.

Term

RA signaling: 

Where is RA synthesized/ 

Definition

1.  RA synthesizing cell (mesoderm): 

•  RA is made from retinol in a two-step 

process involving retinaldehyde 

dehydrogenases (RALDHs

Term
What is the RA receiving cell (neural)?
Definition

2. RA receiving cell (neural): 

•  RA crosses the cell membrane and 

binds to a cytoplasmic receptor, 

CRABP (cellular retinoic acid binding 

protein) 

•  CRABP facilitates entry into the 

nucleus 

•  RA bind to heterodimeric receptors 

•  RA-bound receptors interact with a 

DNA sequence, RARE (retinoic acid 

response elements), to activate 

transcription 

•  RA degraded in cytoplasm by 

CYP26

Term
What is beta catenin?
Definition
- involved inspecific cell type like neural tissues in spinal cord but also axonal outgrowth
Term
What is accutane?
Definition

•  Prescribed for severe Acne 

•  Active ingredient: isretinoin 

(vitamin A analog) 

•  Withdrawn from market in 2009 

•  Potent teratogen at very low doses 

(critical window: first 3-5 weeks of 

pregnancy) 

•  Birth defects are severe 

(microcephaly, neural tube 

defects, craniofacial and 

cardiovascular malformations) 

•  50% of affected children: IQ below 

85 

Term
Not just RA that contributes to transformation of posterior nervous sytem structures. What else is important?
Definition

Wnt also has an important role

- When the beta catenin is in the phosphorylated state, it cant get into the nucleus but Wnt breaks this stage and allows it to get in to interact with the transcription factor. 

 

Wnt = ligand 

Frizzled = plasma membrane receptor 

Dsh = (dishevelled) intracellular component of Wnt receptor complex 

The axin/GSK-3/APC complex promotes the proteolytic degradation of the β-catenin intracellular signaling molecule and some β-catenin, is able to enter the 

nucleus and interact with transcription factors. 

Term
what are the three anti-Wnts?
Definition
•  Cerberus (Cer) 
•  Dickkopf(Dkk1) 
•  Frizzled-related protein (Frzb1) 
Term
What does these Wnt antagonists do?
Definition

they shape the activity gradient. They induce anterior neural tissues.  

• These diffusible signals 

establish a Wntactivity gradient 

in the neural ectoderm (NE) 

where there is more Wntin 

posterior segments. 

• The AP neuraxis is patterned by 

the interplay between 

posteriorizing Wntsand Wnt

antagonists secreted by 

Spemann’s organizer, which are 

higher in rostral segments

Term
What does the three wnt antagonists do?
Definition

Dickkopf: induces ectopic head 

formation (named for the German 

word for “thick-headed, stubborn”)

Frzb1: induces head enlargement 

Cerberus: induces ectopic head 

formation (necessary & sufficient for 

head formation) 

 

Dickkopf is necessary for head formation but 

not sufficient by itself 

Head induction also requires Wnt antagonism 

in combination with BMP antagonism 

Term
What is the role of Hox (homeobox) genes and proteins?
Definition

•  After embryonic segments have formed, Hoxgenes and thus their 

products (Hox proteins) determine the type of subsequent structures 

arising from that segment (e.g. wings, legs or antennae in 

Drosophila and type of rib or digits in humans) 

•  The Hoxgenes are a class of regulatory genes that code nuclear 

proteins, termed homeoproteins that mostly act as transcription 

factors. The protein domain encoded by the homeobox is known as 

the homeodomain (HD). The homeodomain is capable of 

recognizing and binding to specific DNA sequences. Hox proteins 

bind to specific nucleotide sequences on DNA called enhancers 

where they either activate or repress genes. 

•  The same Hox protein can act as a repressor at one gene and an 

activator at another. Hoxgenes can regulate cascades (hundreds) of 

genes simultaneously! Hox genes are phyogentically conserved (you 

can substitute a chicken Hox gene for the same Drosophila Hox 

gene and not alter function)

•  In vertebrates, including humans, retinoic acid regulates differential 

expression of Hox genes along the anteroposterior axis. 

Term
What is the role of Hox in Drosophila?
Definition

•  Individual segments of Drosophilahave 

distinct fates 

•  Early discoveries in embryonic patterning 

exploited segmented body plan and fly 

genetics 

•  Induced mutations in Drosophilato observe 

the effect on segmental developmental 

derivatives (structures) 

•  Genes in the 3' ends of Hoxclusters are 

induced by retinoic acid (RA) resulting in 

expression that is restricted more anteriorly 

in the body compared to 5' Hoxgenes that 

are not induced by retinoic acid resulting in 

expression domains that remain more 

posterior in the body.

Term
What does Mutagenic studies reveal about some mutations?
Definition

 can give rise to‘homeotic 

transformations’(the conversion of one segment into another).

e.g. Hoxmutation “ultrabithorax (Ubx)”

Normally Ubxprevents 3

rd

thoracic segment 

from taking on 2

nd

thoracic segment phenotype. 

Mutation in Ubx results in a loss of function 

(LOF) and induces a segmental transformation: 

Normally: 

3

rd

thoracic segment normally gives rise to 

halteres 

2

nd

thoracic segment normally gives rise to 

wings 

In the Ubxmutant: 

3rd thoracic segment is transformed into 

another 2nd

thoracic segment: 

two sets of wings, no halteres 

Ubxand AbdAcomplex genes 

also repress limb development in 

abdominal segments by inhibiting 

distal-less (Dlx) genes 

Term
What is the mutant Antennapedia?
Definition

•  The mutant, Antennapedia, is a Gain of Function (GOF) mutation, which 

causes legs to grow in place of antennae (shown below on right)

 

•  LOF mutation in antennapedia causes antennae to grow in place of 

second pair of Drosophilalegs

Term
How are Hox genes arranged similarily in flies and mammals?
Definition

anterior genes at 3’end 

posterior genes at 5’end 

•  Drosophila: 8 genes in 2 

complexes 

•  Mouse: many genes in 4 

clusters (a,b,c,d) 

•  Genes are denoted by 

cluster and position within 

the cluster (e.g. Hoxa1) 

•  Paralogs hold the same 

position within each 

cluster: (Hoxa1, Hoxb1, 

Hoxc1, Hoxd1) 

•  Note: Hoxa genes and 

roles in mammalian brain 

are discussed below 

Term

How is the vertebrate hindbrain segmented in early neural development? 

Study the figures in slide 26

Definition
Term
What are Rhombomeres?
Definition

Rhombomeres are repeated, segment-like swellings in the hindbrain 

•  Motor neurons in adjacent pairs of 

rhombomeresinnervate the 

branchialarches (evolutionary 

derivatives of gills: produce tissue in 

face, neck, throat) 

•  These motor neurons form the 

efferent component of cranial nerves 

(I – XII) 

•  Studies of Hoxgene function in 

vertebrates have focused on the 

hindbrain 

Rhombomeres 

Term
Study the image on slide 28
Definition
Term
What does overlapping Hox gene expression do?
Definition
Overlapping Hox gene expression (Hox code) confers rhombomere identity
Term
Deletion of Hoxa1 results in what?
Definition

results in the loss of r5 and a reduction in r4

Abducens (VI) motor neurons are lost and facial (VII) motor neurons are reduced 

Note: Hoxa1 is expressed earlier than Hoxb1 

The nerve that cause the eyes laterally (horizontally) is r6. If you knock it out of the Abducens, this is the consequences. ANy particular rhomdomere will causes a change if it was taken out. 

Term
What happens if Hoxb1 is deleted?
Definition

facial (VII) motor neurons transformed into trigeminal (V

i.e. there is a 

duplication of 

trigmeminal motor 

nerves in facial territory 

Term
WHat happens when retinoic acid antagonists are administered at different concentrations?
Definition

• More posterior 

segments require 

higher conc. of RA to 

develop: 

Rhombomere identity 

depends on the 

gradient of RA 

expression (which in 

turn regulates Hox 

gene activity) 

 

if its very little RA, you reduce the # of rhombomere behind the hindbrain. This changes the activity and changes the hindbrain (basically keeps u alive). 

Term
What are the homeodomain transcription factors?
Definition

are a general feature of specific 

regions of the nervous system 

e.g. Otx2 (forebrain/midbrain) and Gbx2 (hindbrain/spinal cord)

Homeodomain protein expression domains are 

demarcated by sharp borders: 

These borders exist between rhombomeres (Hox 

genes) 

AND at other divisions of the nervous system (other 

homeodomain transcription factors) 

Term
Mechanisms regulating boundary (pattern) formation involves what?
Definition

involve 

variations in cell differentiation, migration and diffusible factor 

expression/release

• Regulation by diffusible factors (e.g. retinoic acid) 

• Cross-repression of differentiation (between different genes & proteins) 

• Differential cell adhesion (contact-mediated cell signaling) 

• Differential gene expression 

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