Talk:2009 Lecture 12

Background Reading

Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. Van Keymeulen A, Mascre G, Youseff KK, Harel I, Michaux C, De Geest N, Szpalski C, Achouri Y, Bloch W, Hassan BA, Blanpain C. J Cell Biol. 2009 Oct 5;187(1):91-100. Epub 2009 Sep 28. PMID: 19786578

"Merkel cells (MCs) are located in the touch-sensitive area of the epidermis and mediate mechanotransduction in the skin. Whether MCs originate from embryonic epidermal or neural crest progenitors has been a matter of intense controversy since their discovery >130 yr ago. In addition, how MCs are maintained during adulthood is currently unknown. In this study, using lineage-tracing experiments, we show that MCs arise through the differentiation of epidermal progenitors during embryonic development. In adults, MCs undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through the proliferation of differentiated MCs. Conditional deletion of the Atoh1/Math1 transcription factor in epidermal progenitors results in the absence of MCs in all body locations, including the whisker region. Our study demonstrates that MCs arise from the epidermis by an Atoh1-dependent mechanism and opens new avenues for study of MC functions in sensory perception, neuroendocrine signaling, and MC carcinoma."

The neural crest epithelial-mesenchymal transition in 4D: a 'tail' of multiple non-obligatory cellular mechanisms. Ahlstrom JD, Erickson CA. Development. 2009 Jun;136(11):1801-12. PMID: 19429784
- Link to single labelled cell migration movies Supplementary Material | movie 1

Specification and connectivity of neuronal subtypes in the sensory lineage Frédéric Marmigère and Patrik Ernfors Nature Reviews Neuroscience 8, 114-127 (February 2007) [1]

Lecture Summary

The following text is extracted and modified from lecture slides and should be used as a "trigger" to remind you of key concepts.

Lecture Summary
- Neural Crest Origin
- Neural Crest Migration
- Neural Crest Derivatives
- Head
- Trunk
- Peripheral Nervous System
- Abnormalities
Online ReferencesUNSW Embryology: Neural Cresthttp://embryology.med.unsw.edu.au/Science/ANAT2341lecture13.htmhttp://embryology.med.unsw.edu.au/Notes/ncrest.htm
Note: not all shown slides used in Lecture
Textbook References
- Larsen - Chapter 4 p74-82 - Chapter 5, experimental methods
- Moore & Persaud - Chapter 4 p61-63 - p71,75, 385, 392 p393-94 (figure showing cell types)
Neural Crest Derivativesmigrate throughout embryo and give rise to many different cellsgangliacranial, dorsal root, sympathetic trunkceliac, renal, plexus in GITglia, schwann cellsmelanocytes (skin)adrenal medulla (chromaffin cells)
Ectoderm DerivativesNeural Crest DerivativesNeural Crest DerivativesBone Morphogenetic ProteinsBMPs secreted growth factorstransforming growth factor beta classTGF beta superfamilyneural induction formation of neural plate border
Neural Crest OriginLateral neural platedorsal neural fold->tube2 main regionshead (CNS)differentiate slightly earliermesencephalic region of neural foldsbody (spinal cord)lateral edges of fused neural tube
Neural Crest Formation
EM Neural Tube
Primary Neurulation
Signals in Neural Crest FormationSuggested signalsOpen neural plate stagessignals from adjacent non-neural ectoderm (arrows) and underlying non-axial mesoderm (arrowheads) are thought to induce regions at neural plate border (black circles). Wnts, FGFs, and BMPs. Closing neural tubeBMPs, and BMP signaling required for neural crest formation (circular arrows)Closed neural tubecells migrate out from dorsal neural tube.neural tube expresses a number of BMPs and Wnts (circular arrows)
CadherinLocalised expression of adhesion moleculesRegulates morphological decisions
Cadherins3 cadherins pattern in chick or mouse embryoPattern changes with timeCells expressing same type of cadherins stick togethersegregate from other cells
Morphogenetic movementsneural tube, notochord, somites, neural crest, and sclerotomesCadherins
Neural Crest Formation
Migration - ModelsDevelopment of the peripheral nervous system from neural crestLeDouarin 80‚ÄôsAnn Rev Cell Biol 4, p375http://sdb.bio.purdue.edu/dbcinema/ledouarin/ledouarin.htmlChicken/Quail transplantationnucleoli to differentiate different speciesfollow path of transplanted cells migrationnow molecularly tag neural crest cells (LacZ)see Larsen: Chapter 5, p107Movie: Chick/Quail Chimera
Chick/Quail Chimera Development
Neural crest cell migration
Neural Crest Generationnot a segregated populationneural plate - epidermis interactionsneural crest cells form at interfacecranial levelsneuroepithelial cells can generate neural crest cells when endogenous neural folds are removedprobably via interaction of remaining neural tube with epidermisneural fold cells multipotential form multiple ectodermal derivativesepidermal, neural crest, and neural tube cellsneural plate response to inductive interactions changes as a function of embryonic age
Neural Crest Trunk Migrationafter leaving neural tubeneural crest migrationmedial pathwaybetween somites and neural tube lateral pathwaybetween somites and epidermis
Neural Crest Migration
Migration Pathways
Zebrafish Neural Crest MigrationLiving Zebrafish studyfirst cells to migrate all choose the medial pathwaycells take medial pathway because repulsion by somiteslateral somite surface triggers a paralysis and retraction of protrusions, contact inhibition or collapsemedial surface does notPartial deletion of somitesusing the spadetail mutation allows precocious entry into lateral pathway only where somites are absentinhibitory cue on somites delays entryResults from high resolution imaging of cells in living embryoJesuthasan Development 1996 Jan;122(1):381-9
Neural Crest Migrationstage 10 (8-11 somites)crest migration in areas of unfused neural foldsthrough focal disruptions in neuroepithelial basement membrane in rostral and pre-otic regionsNo crest migration in post-otic hindbrainstage 11 (16-17 somites)neural folds were fused (pre- and post-otic hindbrain) or in process of fusing (rostral hindbrain)crest cell migration in all 3 areas through breaks in basement membranestage 12 (21 somites)migration essentially complete nearly continuous cranial neural tube basement membranespre-ganglia (trigeminal, facioacoustic and glossopharyngeal) stained with N-CAMUse cell surface markers and ECM adhesive proteinslaminin and collagen-IV in neuroepithelial basement membranesNeural Crest Migration
Specific adhesive pathways
ECM and membrane proteins
Developmental and adult roles
Laminin
Differential neural crest cell attachment and migration on avian laminin isoformspreference for Laminin-G (gizzard tissue) over Laminin-alpha x (heart tissue)
T-cadherin, truncated cadherin, calcium dependent adhesion molecules
Fibronectin
Fibronectin ‚Äì Adhesion Crosslinker
Neural Crest MigrationECM inhibitor pathwaysAggrecans and PG-M/versicans families of hyaluronan-binding proteoglycansS103L chondroitin sulfate proteoglycan
Other FactorsHigh glucose concentrationinhibits migration of rat cranial neural crest cells in vitromay explain some teratogenic effects of diabetic pregnancyNeural Crest Gene Expressioncells leaving neural crest express RhoB protein (green)Cells expressing both HNK-1 and RhoB (yellow)migrating neural crest cells express HNK-1 (red)
After Liu and Jessell 1998
Neural Crest DifferentiationBegins in cranial regionwhen still neural foldIn spinal cordfrom day 22 to 26after closure of caudal neuroporerostro-caudal gradient of differentiation
Neural Crest Regions
Neural Crest - Trunk
Neural Crest LineageNeural Crest- Head
Arch mesenchyme invaded by neural crestgenerating connective tissue componentscartilage, bone, ligamentsarises from midbrain and hindbrain region
Neural Crest- Headmesencephalon and caudal proencephalonparasympathetic ganglia CN IIIconnective tissue around eye and nervehead mesenchymeMeningespia and arachnoid materdura from mesoderm
Movie: Neural Crest cell migrationAvian Cranial Neural CrestCranial Neural Crest MigrationCranial Neural Crest MigrationHox Gene Expression
Neural Crest- Head mesencephalon and rhombencephalon pharayngeal archeslook at Lab notes on neck and headCartilage rudimentsnose, face, middle earFacedermis, smooth muscle and fat
Teethodontoblasts of developing teethrhombencephalonC cells of thyroidcranial nerve ganglianeurons and gliaparasympathetic of VII, IX, Xsensory ganglia of V, VII, VIII, IX, XNeural crest- Spinal Cordperipheral nervous systemdorsal root ganglia (sensory N)parasympathetic gangliasympathetic gangliamotoneurons in both gangliaall associated glia
Cardiac Neural CrestHeartoriginally forms in neck regiondirectly beneath pharyngeal archesacquires cells from neural crestcaudal region of cranial neural crest is sometimes called ‚Äúcardiac neural crest‚Äù Only these neural crest cells can generate endothelium of:aortic arch arteriesseptum between aorta and pulmonary arteryTruncus Arteriosus
Cardiac Neural CrestChickencardiac neural crest lies above neural tube regionrhombomere 7 to spinal cord level apposing somite 3cells migrate into pharyngeal arches 3, 4, and 6 ExperimentNC removed and replaced by anterior cranial or trunk NCCauses cardiac abnormalitiesfailure of truncus arteriosus to separate into the aortic and pulmonary arteriesCardiac neural crest already determined to generate cardiac cellsother neural crest regions cannot substitute Kirby 1989; Kuratani and Kirby 1991Cardiac Neural CrestMicecardiac NC cells express transcription factor Pax3
Pax3 Mutant defectspersistent truncus arteriosusfailure of aorta and pulmonary artery to separatedefects in thymus, thyroid, and parathyroid glandsConway et al. 1997
Humans and MiceCongenital heart defectsoften occur with defects in parathyroid, thyroid, or thymus glandsMaybe all are linked to defects in migration of cells from neural crest
Heart FormationCommunication Between Migrating Cardiac Neural Crest CellsGrowth Factor control of LineageSchwann Cell Lineage
Neural Crest AbnormalitiesExamplesKit- PiebaldismDiGeorge syndrome (DGS)Hirschsprung DiseaseOMIM119 entries ‚Äúneural crest‚Äùhttp://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=OMIM
Kit- PiebaldismPiebaldism caused by mutation in KIT geneKit protein essential for proliferation and migrationneural crest cellsgerm cell precursorsblood cell precursors
DiGeorge syndrome (DGS)Hypocalcemiaparathyroid hypoplasiathymic hypoplasiaheart outflow tract defectsAbnormal cervical neural crest migration into derivatives of pharyngeal arches and pouchesMost cases a deletion of chromosome 22q11.2DiGeorge syndrome chromosome region (DGCR)
Hirschsprung Disease
- congenital disorder described by Hirschsprung (1888)
- "[My first specimen] is a colon, but a colon of such a size that it will no doubt surprise you to learn that it comes from a
- child only 11 months old when it died‚Ä¶. Only [the] rectum was not dilated, nor indeed subject to any obstruction."
- Hirschsprung disease, aganglionic colon, megacolon
- absence of enteric ganglia
- along a variable length of intestine
References
- Early induction of neural crest cells: lessons learned from frog, fish and chick.
- Aybar MJ, Mayor R. Curr Opin Genet Dev. 2002, 12:452
- N-CAM labelling of cranial neural crest cells
- Peterson, Anatomy & Embryology 1996, 194:235-46
- Development of the peripheral Nervous system from the neural crestAnn Rev Cell Biol 4 p375
- Living Zebrafish Studies
- Jesuthasan, Development 1996;122(1):381-9
- Chicken Studies Bronner-Fraser M PNAS 1996 Sep 3;93(18):9352-7
Following Slides - not Examinable
Tooth DevelopmentMouse/chick chimeras
Hens ‚Äúteeth‚ÄùTeeth lost in birds 70-80 million years agoodontogenic capacityLost avian cranial neural crest-derived mesenchymeoral epithelium retains signaling properties requiredodontogenic capacity of ectomesenchymeneural tube transplantations from micereplace chick neural crest cell populations with mousemouse/chick chimeras show evidence of tooth formationavian oral epithelium able to induce a non-avian developmental program in mouse NC-derived mesenchymal cells
NC Pluripotency ExperimentTemporal analysis of NC induction
Gradient model of NC induction(a) Medio-lateral gradient of BMPs (red) established in ectoderm specifying neural plate border as anterior neural fold (pale purple) at a threshold concentration(b) Posteriorizing signals (green curve) correspond to activities of Wnts, FGFs and RA transform most posterior part of neural plate border into prospective NC cells (dark purple) signals generated in a gradient-like manner higher levels in posterior part of ectoderm lower levels in the anterior region, also kept low by anti-posteriorizing signals, such as Dickkopf and Cerberus (green curve), produced by anterior region of the embryo(c) Once neural tube is closed Some initial inductive signals expressed in dorsal region epidermis, neural crest and dorsal neural tube signals are required to maintain specification of NC cells process known as late step of NC inductionexpression of BMPs and Wntsevidence that RA is expressed in hindbrain region, but no expression of this molecule has been reported in NCA, anterior; P, posterior; M, medio; L, lateral; D, dorsal; V, ventral.
NC Anterior Posterior Patterning
NC Schwann Cell Lineage