Van Raamsdonk Lectures Flashcards
When does primary neurulation occur in humans?
Day 18-23
When does secondary neurulation occur in humans?
Day 28-48
What closure point(s) is/are affected in exencephaly/anencephaly?
Closure points 2 and 3
The lack of which transcription factor is responsible for exencephaly/anencephaly?
Grhl3
What closure point(s) is/are affected in craniorachischisis?
Closure point 1
The lack of which transcription factor leads to cranioarchischisis?
Celsr1
Deficiency in which vitamin is linked to NTDs?
Vitamin B9 (folate)
What are the 6 criteria for determining whether something is a teratogen?
- Abrupt increase in frequency of a defect or syndrome 2. Increase of syndrome associated with agent 3. Agent was present during critical stage 4. Agent produces birth defects in animal models 5. Agent can cross placenta (exceptions) 6. Mechanism of teratogenesis makes biological sense
What were 4 reforms made to drug regulation following the thalidomide disaster?
Federal regulation of clinical trials, informed consent prior to enrolment in clinical trial, pre-clinical trials must include more than one animal model, companies must do more to show that drugs are safe before approval
What is the thalidomide sensitive window?
4th week of pregnancy
Which cells spread Zika virus around the fetus?
Hoffbauer cells
What is the critical period of Zika virus?
12-16 weeks
What is the proposed mechanism for thalidomide syndrome?
Thalidomide causes CRBN to target p63 as a neosubstrate; CRBN is an E3 ubiquitin ligand, so it targets p63 for degradation; p63 levels maintain high FGF in AER, which is necessary for limb development; without high FGF, phocomelia occurs
What is the proposed mechanism for Zika virus causing microcephaly?
ZIKV unregulates TP53 protein, which causes apoptosis through S-phase arrest
What are the pluripotent factors expressed by neural crest cells?
Nanog, Oct4, and Klf4
What signalling molecules induce neural crest cells?
Intermediate FGF, intermediate Wnt, intermediate BMP
Which tissue is made where BMP signalling is high?
Skin
Which signalling molecules induce EMT in neural crest cells?
BMP and Wnt cascade
What are the two key TFs for EMT in cranial neural crest cells?
Snail and Foxd3
Which are the negative regulators of neural crest cell migration?
Ephrins (bind ephrin receptors of neural crest cells) and neurophilins (bind semaphorin on neural crest cells)
Which stream of neural crest cells makes PA1?
Stream 1
Which stream of neural crest cells makes PA2?
Stream 2
Which stream of neural crest cells makes PA3 and PA4?
Stream 3
Which structures does PA1 make?
maxilla, mandible, zygomatic bone, malleus, incus
Which structures does PA2 make?
Stapes, hyoid
Which PAs contribute to the heart?
PA3, PA4, and PA6
Hox patterning code for PAs
No Hox genes = PA1
Hox2 = PA2
Hox2 + Hox3 = PA3
Hox2 + Hox3 + Hox4 = PA4
What happens if Hox2 is deleted?
PA1-like structures are produced by PA2, PA3, and PA4
What does ectopic expression of Hox2 in PA1 cause?
Development of PA2-like structures
What happens if Hox3 is deleted?
Malformations in PA3 and PA4 only
Dlx patterning codes for PA1
Dlx1/2 = dorsal (maxilla) Dlx1/2/5/6 = intermediate Dlx1/2/5/6/3/4 = ventral (mandible)
What is the result of a Dlx1/2 deletion?
Causes problems with maxilla formation
What is the result of a Dlx5/6 deletion?
2 maxilla jaws formed as mirror images instead of a maxilla and a mandible
Which signalling molecule is important for mandible formation?
Endothelin 1 signalling, as it induces the expression of Dlx5/6
What is the result of a KO of endothelin 1?
Dlx5/6 is not induced; therefore, mandible becomes maxilla
What is the molecular pathway involving endothelin1, Dlx5/6, Hand1/2, and Bapx1?
Endothelin 1 —> Dlx5/6 —> Hand1/2 —] Bapx1
Endothelin —> Bapx1
What is the function of Bapx1?
Specifies correct position for joint of upper/lower jaw
What is the result of ectopic expression of Hand1/2 in maxilla?
Maxilla develops as mandible instead
What structures do trunk neural crest cells form? (5 structures)
Neurons (sensory and autonomic), enteric nervous system (controls peristalsis and secretion of digestive enzymes, regulates blood flow and produces dopamine), glial cells, medullary cells of adrenal gland, melanocytes
Which cells take neural crest cell path 1 in the trunk?
All neural crest cells (incl. melanocytes)
Which cells take neural crest cell path 2 in the trunk?
Only neural crest cells that become melanocytes
What type of epigenetic mark is H3K27ac?
Activating mark
What type of epigenetic mark is H3K4me2?
Activating mark
What type of epigenetic mark is H3K27me3?
Repressing mark
