Neural Crest Cells Flashcards
(23 cards)
What is the role of EMT in neural crest migration? What signals regulate it?
EMT allows NCCs to delaminate from the dorsal NT
- Wnt, Notch, BMP & FGF pathways trigger EMT
- downregulate cadherin = cells lose cell-cell adhesion & increase in motility and invasiveness
- upregulation of Snail, Twist, Slug (EMT transcription factors) - promote EMT changes
How do Rho GTPases coordinate front-rear polarity during NCC migration?
- Rac1/Cdc42 promote front protrusions
- RhoA drives rear contraction via actomyosin contractions (retractions)
together drive a forward directional movement of individual NCCs with front-rear polarity
What is contact inhibition of locomotion (CIL), and how does it affect NCC migration?
CIL is when cells make contact - repolarise and move away
- RhoA activated at contact site between both cells = induces actomyosin contractions; retraction
- Rac1 inhibited at contact sites = inhibits protrusions
repulsion & repolarisation with CIL ensures migration of NCCs away from each other to guide migratory NCC streams
Why is co-attraction important in NCC migration, and what pathway is involved?
co-attraction balances out CIL - prevents cells from scattering after CIL, prevents cell dispersion
involves NCCs secreting C3a (complement protein) & C3aR (receptor) - signalling maintains stream cohesion as NCCs attract each other
What is the ‘run and chase’ mechanism in NCC migration?
ectodermal placode cells secrete SDF1 - attracts NCC (“chase”)
upon contact with NCCs - placodes move away (“run”) - creates a dynamic movement pulling NCCs forward with constant ‘run and chase’
How do directional migration and collective behaviour emerge in neural crest cells?
integrated signals of CIL, co-attraction, ECM interactions and mechanical environment/confinement promotes overall forward directional movements of NCCs in a stream
- leading NCCs of stream sense environmental cures - form protrusions using Rac1 expression
- leading cells move forward, responding to external signals
- trailing cells follow due to co-attraction, still experience CIL with other NCCs form different streams
what are the 5 stages of NCC induction?
neural plate induction
neural plate border formation
neural crest specification
neural crest migration
neural crest differentiation
describe the process of neural crest cell induction
- neural plate induction
- during gastrulation, ectoderm is patterned into neuroectoderm, non-neural ectoderm & neural plate border
- BMP4 expressed across ectoderm; dorsal-organiser secretes BMP antagonists & inhibits BMP activity in that region - neural plate border formation
- regional differences in BMP4 levels lead to distinct tissue fates
- dorsal region near organiser (low BMP4) = neural plate
- high BMP4 (away from organiser; ventral) = epidermal fate
- intermediate BMP4 (middle) = neural plate border (future site of NCC formation) - neural crest specification
- neural plate border between neural & non-neural ectoderm
- NPB receives FGFs, Wnts, RA and BMP signals
- activates key TFs: Pax3/7, Dlx5/6, Msx1 - specific to border region, reinforce NPB identity, suppress neural/epidermal fates - neural crest migration
- NPB TFs induce neural-crest specifier genes: Sox9/10, Snai1/2, FoxD3, id, twist, ets1
- specifier genes program pre-migratory NCs (initiate EMT) - positioned at tips of dorsal NT after NT closure - neural crest differentiation
- pre-migratory NCCs undergo EMT = lose epithelial traits, become migratory mesenchymal cells (no polarity, no cell junctions)
- NCCs express Snai1/2, Sox9/10, RHO GTPases = promote migratory behaviour
- NCCs leave & migrate to specific locations along AP axis of embryo
migrating NCCs reach target regions, diverse differentiation = cell fate decisions guided by specific combos of TFs and environmental signals q
Where do cranial neural crest cells (NCCs) originate, and what do they contribute to?
originate from forebrain to rhombomere 5
- migrate into head & neck region
- populate first 3 pharyngeal arches
- contribute to craniofacial structures (facial bones, skull, cranial nerves, teeth, and ear structures)
What structures are found in each pharyngeal arch?
each pharyngeal arch contains
- a mesodermal core
- surrounded by neural crest-derived mesenchyme
- lined externally by ectoderm and internally by endoderm
- includes an aortic arch artery.
What are the contributions of cranial and cardiac NCCs to pharyngeal arches 1–3?
Arch 1: Jaw, maxilla, ear bones, innervated by CN V (trigeminal nerve).
Arch 2: Hyoid bone, innervated by CN VII (facial nerve).
Arch 3: Structures associated with CN IX (glossopharyngeal nerve).
Cardiac NCCs contribute to the development of the first three arches and parts of the heart.
How do NCCs migrate from rhombomeres into pharyngeal arches?
Cranial NCCs migrate in distinct streams from specific rhombomeres into pharyngeal arches.
Odd-numbered rhombomeres (R1, R3, R5) produce fewer NCCs - adjacent NCC streams must not mix to ensure correct craniofacial development.
What is the role of Eph/Ephrin signalling in NCC migration?
Eph/Ephrin signalling prevents mixing between NCCs from adjacent rhombomeres.
- even-numbered rhombomeres express EphrinB2 (ligand)
- odd-numbered rhombomeres express EphB receptors
causes contact-dependent repulsion and maintaining separate, non-overlapping NCC streams
Eph/ephrin signalling is conserved in frogs, chicks, zebrafish, and mice
- chicks = additional repulsive signalling mechanisms (ventral Eph/Ephrin and dorsal ErbB4) ensure precise NCC migration and craniofacial patterning
What are Hox genes and their general role in development? How do Hox genes influence cranial NCCs and pharyngeal arches
Hox genes = evolutionarily conserved TFs with homeobox domains that regulate AP patterning
- organized in Hox A–D clusters and follow collinearity: 3’ genes are expressed more anteriorly in the embryo
Cranial NCCs inherit Hox gene expression from their rhombomere of origin and maintain that “Hox code” during migration.
- Hox code defines the identity and fate of rhombomeres, cranial NCCs, pharyngeal arches, and their derived structures
jaw formation & cranial NCCs
Pharyngeal Arch 1 (PA1) is crucial for jaw development and must be populated by Hox-negative neural crest cells (from rhombomeres 1 and 2).
Hox-negative identity is essential: it allows NCCs to properly differentiate into jaw structures (e.g., mandible, maxilla, ear bones).
Hoxa2 expression starts just behind PA1 (in more posterior arches).
Loss of Hoxa2 in R4 NCCs → posterior structures take on a jaw-like identity (duplicated lower jaw).
Ectopic Hoxa2 expression in PA1 → jaw suppression and defective craniofacial development.
Therefore, correct Hox gene boundaries are vital: jaw formation depends on keeping PA1 free of Hox gene expression.
cardiac neural crest cells
CNCCs arise from rhombomeres 7/8 to somites 1-3 and migrate through pharyngeal arches 3, 4, 6.
They contribute to outflow tract (OFT) septation, remodelling aortic arch arteries, and connective tissue of the thymus, thyroid, and parathyroids.
CNCC defects cause congenital heart defects like persistent truncus arteriosus, double outlet right ventricle, and transposition of the great arteries.
trunk NCCs - origin? migration patterns?
origin; between the vagal and sacral NCC regions
migration
- early = between dorsal NT and somite
- mid = anterior part of somite (sclerotome) - not posterior due to inhibitory cues
- late = within somite = give rise to dorsal root ganglia
- late = dorsolateral pathway = melanocytes
What is the role of trunk NCCs in the development of sensory neurons and melanocytes?
Trunk NCCs that migrate via the dorsolateral pathway give rise to melanocytes - skin and hair pigmentation
Trunk NCCs that enter somites form the dorsal root ganglia (DRG) - house sensory neurons that connect the body to the CNS
What are the key signaling pathways that regulate trunk NCC migration?
Neuropilin–Semaphorin signaling: Directs NCCs’ migration, repelling them from the posterior somite during mid-stage migration.
Rho signaling: Controls contact inhibition of locomotion, guiding NCCs to move in the correct direction.
Pax3: A paired homeobox transcription factor critical for NCC migration and differentiation; mutations in Pax3 can lead to NCC developmental defects.
c-Kit: A receptor tyrosine kinase involved in melanocyte development.
Patch gene (PTCH): Regulates growth and differentiation by binding to PDGF, particularly in melanocyte development.
How does Neuropilin–Semaphorin signaling influence trunk NCC migration?
Neuropilin-Semaphorin signaling helps guide NCCs’ migration by repelling them from the posterior somite during mid-stage migration, ensuring NCCs avoid inhibitory cues in the posterior part of the somite.
What role does Rho signaling play in NCC migration?
Rho signaling controls contact inhibition of locomotion, a mechanism that ensures NCCs move in the right direction by preventing inappropriate movement and keeping them on their designated migration path.
What is neuroblastoma, and what is its cellular origin?
Neuroblastoma is a type of cancer that arises from sympathoadrenal NCC progenitors. These progenitors normally differentiate into sympathetic neurons or chromaffin cells but become cancerous in neuroblastoma, leading to uncontrolled cell proliferation.
How do genetic drivers like MYCN and ALK contribute to neuroblastoma and disrupt NCC differentiation?
MYCN: MYCN is an oncogene that promotes proliferation and inhibits apoptosis. Amplification of MYCN leads to uncontrolled cell division, preventing the normal differentiation of sympathoadrenal neural crest cells (NCCs) into neurons and chromaffin cells. This results in the formation of neuroblastoma tumors.
ALK: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase. Mutations in ALK, particularly germline mutations, are often found in familial neuroblastoma. Mutant ALK activates downstream signaling pathways like PI3K-AKT and RAS-MAPK, which drive abnormal proliferation and survival of NCC-derived tumor cells. This disruption prevents proper differentiation of NCCs into functional neural or adrenal cells, leading to neuroblastoma formation.
These genetic alterations lead to disrupted differentiation and excessive proliferation, both hallmark features of neuroblastoma, by interfering with the normal developmental pathways of NCCs.
