W4L2 Thu Human development 2

Question 1

Neurulation

Answer 1

-After gastrulation, the next major event is NEURULATION
-Firstly a region of the ectoderm thickens into the NEURAL PLATE .
-This tissue then undergoes epithelilal folding to eventually form the NEURAL TUBE (D)

Question 2

Step in neurulation

Answer 2

-Elongation
-Folding
-Elevation of neural crest
-Convergence
-Closure

Question 3

Neural tube defects

Answer 3

-Neural tube defects (NTDs) affect 1 in every 1000 pregnancies (2 nd most common birth defect, after congenital heart defects).
-anencephaly - results from a failure to close the anterior neuropore
-spina bifida - results from a failure to close the posterior neuropore

Question 4

Cell change in neurulation

Answer 4

-In the region between the neural plate and the epidermis a distinct type of cell is specified. These cells undergo an EPITHELIAL MESENCHYMAL TRANSITION (EMT) and begin to migrate throughout the body
-This EMT is dependent on the Snail family gene SLUG (also called SNAIL2).

Question 5

The neural crest – “the fourth germ layer”

Answer 5

-They move throughout the body and differentiate into many types of cells.
-For this reason, they are sometimes thought of as the fourth germ layer.

Question 6

Waardenburg’s syndrome

Answer 6

• hypo-pigmentation (white forelock, blue eyes)
• sensorineural deafness

Question 7

Cause of waardenburg syndrome

Answer 7

-Pedigree analysis of several families with the syndrome mapped the mutation to the short arm of chromosome 3

Question 8

Mice are a genetic model for waardenburg syndrome

Answer 8

-Mutations in the microphthalmia gene (mitf) in mouse cause deafness, a white patch of fur and eye abnormalities. Subsequent testing found that the human orthologue of MITF was located in the mapped region of chromosome 3, and was mutated in the patients with Waardenburg syndrome.

Question 9

Common phenotypes reveal genetic pathways

Answer 9

Isolation of other mutants with the same phenotype (e.g. receptor tyrosine kinase, Kit) helped determine the genetic pathways that specify the melanocyte lineage.
Recently it was also found that the EMT-factor, SLUG, which drives the neural crest EMT also causes these phenotypes in both mice and humans.

Question 10

Melanocyte development signaling pathways

Answer 10

• signalling lead to activation of multiple gene:
  -PAX3 involve in migration of neural crest
  -MITF-M proliferate and differentiate into many cells
  -SNAI2 repressor c-kit (involve in the activation of the pathway) negative control

Question 11

Melanocytes and waardenburg

Answer 11

-melanocytes are found in the basal parts of the epidermis.
-They make the pigment melanin, which is passed on to keratinocytes.
-The white forelock is due to a failure of MELANOCYTES to migrate out to the tip of the developing forehead.
-The deafness is because melanocytes help form part of the inner ear.

Question 12

Neural tube pattern formation

Answer 12

The neural tube is patterned by opposing gradients of Sonic hedgehog (Shh) which is expressed in the notochord and floor plate and BMP4 (a TGFbeta family molecule) expressed in the epidermis and roof plate.
-local concentration shape development

Question 13

Holoprosencephaly (HPE)

Answer 13

-HOLOPROSENCEPHALY is the most common structural anomaly of the developing forebrain, which results from incomplete cleavage of the fore-brain
-The severity can range from cyclopia, with a single eye and proboscis forming, to midline facial clefts, or, in the mildest cases, a single central incisor.
-Holoprosencephaly occurs quite frequently, having been observed in 1:250 conceptuses. However, the birth prevalence is only 1:8000 live births

Question 14

The sonic hedgehog pathway in ventral midline

Answer 14

-Sonic hedgehog is expressed at the ventral midline
-This represses expression of genes such as Pax6, that specify lateral cell fates (such as the cells in the eye field).
-In the absence of Shh the brain hemispheres don’t separate and genes such as Pax6 are expressed in the central area only.

Question 15

Pax6 expression in Shh-/- mutants

Answer 15

WT: Pax6 is normally expressed in the lateral regions
Shh mutant: Pax6 is now expressed in the ventral region

Question 16

The Shh pathway and brain hemispheres

Answer 16

-When the Shh-pathway is not activated due to mutations or drug-inhibitors as above, structures that normally develop bilaterally such as the eye field and nostril fail to separate.
-This results in the extreme form of holoprosencephaly that produces cyclopia

Question 17

Segmentation in vertebrates

Answer 17

-Radiograph of a patient with Spondylocostal dysostosis (SCDO1), showing the severe axial skeletal malformations that are associated with a mutation in the DLL3 gene.
-DLL3 (Delta Like 3) is a ligand that activates the Notch pathway

Question 18

Segmentation

Answer 18

-Neural tube and SOMITES revealed by peeling away the surface ectoderm
-Somites come from mesodermal cells which self-organise into an epithelium
-they undergo an MET
-control by Nothc pathway

Question 19

clock and wavefront

Answer 19

-Clock is a positive factor that control gene expression
-Wavefront is a negative factor
There must be no wavefreont for clock to work

Question 20

Somite formation involves a genetic “clock”

Answer 20

• Notch pathway (contain clock) also active Lfng
  -Lfng repress Notch, creating a cyclic pattern

Question 21

What cause wavefront regression

Answer 21

-the regression of primitive streak
–the primitive streak prevent FGF formation but as it regress (moves posterior)
-FGF level are now low enough for somitogenesis to occur

Question 22

congenital mirror movement cause

Answer 22

• French Canadian (FC) family with isolated congenital MM (CMM).
• Pedigree analysis suggested autosomal dominant inheritance.
• A genome-wide linkage analysis identified a 2.5 Mb region containing three known genes, including the axon guidance receptor, DCC (deleted in colorectal carcinoma).
• Sequencing DCC revealed a mutation in a splice donor sequence which resulted in skipping of exon 6 and a frameshift mutation introducing a premature STOP codon.

Question 23

DCC role

Answer 23

-DCC is a receptor for Netrin, also attracted by it
-Netrin-1 diffuses outwards from the floor plate.
-Neurons expressing the DCC receptor are attracted to the source of the Netrin-1.
-Netrin-1 activates DCC which results in internal cytoskeletal changes.
-These cause the neuron to extend.

Question 24

A hypothetical model for mirror movements

Answer 24

• Normally, neuron follow different guidance cue form synapse with motor neuron on the contralateral side
  -In the absence of DCC, some of the neurons will fail to cross over
  -As all their navigational cues still work, it will also go to the same side
  -when neuron is activated, contration of muscle in both side