Bio 127 - Section IIIOrganogenesis

The Neural Crest and Axonal SpecificationGilbert 9e – Chapter 10

Student Learning Objectives

1. You should understand that the neural crest is an evolutionary advancement unique to vertebrates.

a. Led to jaws, face, skull, sensory neural ganglia

b. Transient structure: exists briefly at neural tube closure

2. You should understand that the neural crest is specified into four overlapping regions along the anterior-posterior axis:

a. Cranial neural crest

b. Cardiac neural crest

c. Trunk neural crest

d. Vagosacral neural crest

Student Learning Objectives

3. You should understand that most cells of the neural crest are either multipotent progenitor cells or are already determined to a fate.

a. Large majority of early chick cranial NC can form all cranial fates but only ~10 of the total population that migrates out.

b. Nearly half of chick trunk NC are restricted to one fate

c. Other cells from chick trunk NC can produce:

1. sensory neurons

2. melanocytes

3. adrenomedullary cells

4. glia

4. You should understand that it is unknown if any NC population is a true stem cell, capable of generating stem cells or multiple progenitors

Around the time of neural tube closure...

Neural crestcells migratelaterally and ventrally fromthe dorsal sideof the tube.

Usually the migration is a ‘fire drill’ and all cells leave the a tube...

Distances can varyfrom short to verylong migrations.

Anterior-Posterior patterning of tube extends to the crest

• Vagosacral NC

Cranial NC

Cardiac NC

Trunk NC

Sacral NC

Vagal NC

Cranial Neural Crest Craniofacial Mesenchyme chondrocytes

osteoblasts of head and face

cranial neurons

glia

fibroblasts, face connective tissue

Pharyngeal Mesenchyme thymic cells

odontoblasts of tooth primordia

bone of inner ear and jaw

Cardiac Neural Crest Otic Placode to Third Somite melanocytes

neurons

cartilage

connective tissue

smooth muscle of outflow

connective tissue of outflow

cardiac septal mesenchyme

Trunk Neural Crest Ventrolateral Anterior Sclerotome dorsal root sensory ganglia

sympathetic ganglia

adrenomedullary cells

aortic nerve clusters

Dorsolateral melanocytes

Vagosacral Neural Crest Somites 1-7, Posterior to Somite 28 parasympathetic neurons of gut

Neural Crest Cell Fates

Anterior-Posterior patterning of tube extends to the crest

Your starting positionlimits (specifies) yourfate choices and yourexperiences on the roadchoose (determine) the one.

Figure 10.17 The influence of mesoderm and ectoderm on the axial identity of cranial neural crest cells and the role of Hoxa2 in regulating second-arch morphogenesis

Figure 10.10 Cranial neural crest cell migration in the mammalian head

Midbrain osteoblasts of f frontonasal process FGF, BMP, Edn-1, Nppc, Ihh Twist, Snail, Runx2

Head and 1st Arch myoblasts of facial muscles FGF Twist, Snail,

Rhomb 1,2, 3 osteoblasts, incus & malleus FGF, BMP, Edn-1, Nppc, Ihh Twist, Snail,Runx2

1st Pharyngeal Arch osteoblasts of jaw FGF, BMP, Edn-1, Nppc, Ihh Twist, Snail,Runx2

neurons of trigeminal ganglion FGF, neurotrophin, GDNF Twist, Snail

neurons of ciliary ganglion FGF, neurotrophin, GDNF Twist, Snail

glial cells FGF, neuregulin, Edn-3 Twist, Snail

fibroblasts, face connective tissue FGF Twist, Snail

odontoblasts of tooth primordia FGF, BMP Twist, Snail, Barx1, Msx1,2

Rhombomere 3, 4, 5 chondrocytesof hyoid FGF, BMP Twist, Snail, Osteopontin

2nd Pharyngeal Arch osteoblasts, stapes of inner ear FGF, BMP, Edn-1, Nppc, Ihh Twist, Snail, Runx2

neurons of facial ganglion FGF, neurotrophin, GDNF Twist, Snail

glial cells FGF, neuregulin, Edn-3 Twist, Snail

Rhombomere 6-8 chondrocytesof hyoid BMP Twist, Snail, Osteopontin

3rd and 4th Arches thymic cells FGF Twist, Snail

thyroid cells FGF Twist, Snail

parathyroid cells FGF Twist, Snail

clavicular tendon FGF Twist, Snail

thymic cells FGF Twist, Snail

Cranial Neural Crest

Cardiac neural crest

Pax3 in outflowtract arteries

Contribution tocardiac septum

Cardiac Neural Crest melanocytes FGF, Steel, Edn-3, a-MSH Twist, Snail, Pax3

Otic Placode to neurons FGF, neurotrophin, GDNF Twist, Snail, Pax3

Third Somite chondrocytes BMP Twist, Snail, Pax3

fibroblasts, heart connective tissue FGF Twist, Snail, Pax3

3rd , 4th, 6th Arches smooth muscle of outflow FGF Twist, Snail, Pax3

fibroblasts, outflow connect. tissue FGF Twist, Snail, Pax3

cardiac septal mesenchyme FGF Twist, Snail, Pax3

Cardiac Neural Crest

The Trunk Neural Crest

The cells of the Trunk NC canhead off one of two directions

(the other is the ventral pathway)

Trunk neural crest cell migration

Some individual cells cancontribute to multiple fates

Ventrolateral dorsal root sensory ganglia FGF, neurotrophin, GDNF Twist, Snail

Anterior Sclerotome sympathetic ganglia FGF, neurotrophin, GDNF Twist, Snail

adrenomedullary cells FGF Twist, Snail

aortic nerve clusters FGF, neurotrophin, GDNF Twist, Snail

glia, Scwann cell FGF, neuregulin, Edn-3 Twist, Snail

Dorsolateral melanocytes FGF, Steel, Edn-3, a-MSH Twist, Snail

Trunk Neural Crest

Ventrolateral cell migration through anterior sclerotome only

Restriction due to the ephrin proteins of the sclerotome

Anterior-Posterior patterning of tube extends to the crest

• Vagosacral NC

Cranial NC

Cardiac NC

Trunk NC

Sacral NC

Vagal NC

Somites 1-7Posterior to Somite 28

parasympathetic neurons of gut FGF, neurotrophin, GDNF Twist, Snail, Phox2b

Vagosacral Neural Crest

Figure 10.8 Entry of neural crest cells into the gut and adrenal gland

Figure 10.18 Plasticity and pre-patterning of the neural crest both play roles in beak morphology

Neuronal Specification and Axonal Specificity

• 100 billion neurons in the adult– 300 billion born!– All with a single axon, one or a few synapses– All with a single phenotype, neurotransmitter

• Making the right synapse is critical– Motor neurons better find a skeletal muscle– Retinal neurons better find the optic tectum

Neuronal Specification and Axonal Specificity

1. Induction and patterning of brain region

2. Birth and migration of neurons and glia

3. Specification of cell fates

4. Guidance of axons to specific targets

5. Formation of synaptic connections

6. Competitive rearrangement of synapses

7. Survival and final differentiation by signal

8. Continued plasticity throughout life

Heirarchical Specification

epidermis neural crest neuroepithelium

neuron glia ependyma

ectoderm

motor sensory interneuron

blocking BMP

Delta-Notch

Shh/TGF-B

jaw forelimb hindlimb tail

Hox genes

Heirarchical Specification

hindlimb

columns of terni (CT) medial motor columns (MMC)

lateral motor columns (LMC)

lateral subdivision medial subdivision

birthdayretinoic acid

cadherinsLim family TF

Isl-2, Lim-1express Eph-A4

repelled by ephrin-A5forces them into hamstring

Isl-1, Isl-2express neuropilin-2

repelled by semaphorin-3Fforces them quadriceps

axial muscles

Lhx-3 TF

express FGF-Rpositive chemotaxis

Guidance of Axons to Specific Targets

signals in the membranes of cells along the migratory path

Guidance of Axons to Specific Targets

semaphorin 3expressing cells

semaphorin 3expressing cells

Ephrins and semaphorins can cause the growth cone to collapse

Guidance of Axons to Specific Targets

guidanceof thegrowth cone

Guidance of Axons to Specific Targets

Netrin is a secreted chemotactic signal for axons

Remember DSCAM? 38,016 splice variants in Drosophila

Guidance of Axons to Specific Targets

Few neuronal axons cross the midline of the CNS creating the hemispheres

Robo-1is repelled

Slit issecreted

Robo-3overcomesRobo-1

Guidance of Axons to Specific Targets

BMPs aresecreted from targets,differentBMP receptorsguide branchesto differenttargets

Formation of Synaptic Connections

Reciprocal induction

Requires synaptic transmission

Formation of Synaptic Connections

Multipleaxonscompetefor finalinnervation

Survival and final differentiation by signal

• Apoptosis is often a dominant influence– More than half of the neurons may die

regionally, two-thirds of the total born!– This is less consistent across species than

most neural development events• 80% of cat retinal ganglion cells die• 40% in chick• 0% in fish, amphibians

Survival and final differentiation by signal

• Neurotrophic factors block default apoptosis

• Huntington’s corea is a loss of Huntingtin protein which upregulates BDNF and the survival of striatum neurons– coordinate movement, balance, walking

• Parkinson’s disease is death of dopaminergic neurons which respond to GDNF and CDNF – therapy?

Continued plasticity throughout life

• Many organisms have behaviors before birth

• We can alter synaptic connections thru life– Less so when we get older