Head and Cranial Neural Crest

Head and Cranial Neural Crest

• The head mostly comes from the cranial neural crest, which includes neurons, glia, melanocytes, muscle cells, teeth, cartilage, and bones
• Cranial neural crest cells migrate from midbrain and hindbrain anterior to rhombomere 8 into pharyngeal arches

Derivatives of the Pharyngeal Arches

• The Incus and malleus are from neural crest, as is the mandible, maxilla and temporal bone regions
• Jaw muscles, floor of mouth, muscles of the ear and soft palate derive from the mesoderm
• Maxillary and mandibular divisions of the trigeminal nerve (V) derive from the neural tube
• Stapes bone of the middle ear, styloid process, and part of hyoid bone of neck originate from neural crest
• Muscles of facial expression, jaw and upper neck muscles derive from the mesoderm
• The facial nerve (VII) derives from the neural tube
• Lower rim and greater horns of hyoid bone are from neural crest
• The stylopharyngeus muscle derives from the mesoderm, elevating the pharynx
• The glossopharyngeal nerve (IX) derives from the neural tube.
• Laryngeal cartilages derive from lateral plate mesoderm
• The constrictors of the pharynx and vocal cords are from the mesoderm
• The superior laryngeal branch of the vagus nerve (X) derives from the neural tube
• The fifth arch degenerates in humans
• Laryngeal cartilages derive from lateral plate mesoderm
• Intrinsic muscles of larynx derive from the mesoderm
• The recurrent laryngeal branch of the vagus nerve derives from the neural tube

Cranial Crest Cell Migration Pathways

• Neural crest cells from the midbrain and rhombomeres 1 and 2 migrate to first pharyngeal arch to form the mandibular arch
• They become jawbones, the incus and malleus ear bones, and various nerves
• Other cells enter the head and form the frontonasal process

The Cranium & Neural Crest Cells

• Neural crest cells form most of the cranium, the vertebrate skull
• Cranial bones are intramembranous, created by calcified spicules directly in connective tissue
• The front of the head comes from the neural crest, while the back joins both neural crest and head mesoderm

Cardiac Neural Crest

• The heart originally forms in the neck beneath the pharyngeal arches
• Cardiac neural crest resides in the caudal part of the cranial neural crest and is responsible for the endothelium of aortic arch arteries
• It also forms the septum between the aorta and pulmonary artery
• Cardiac neural crest cells also form other neck structures such as thyroid, parathyroid, thymus glands and the carotid body
• In mice, cardiac neural crest cells express Pax3
• Cardiac neural crest defects also produce defects in the thyroid, parathyroid, and thymus glands, plus pigmentation disorders in humans and mice

Neurons

• Neurons can generate extremely complex neural networks
• Each neuron could have the potential to interact with thousands of others

Axon Growth Cones

• Axons grow via growth cones, their locomotion apparatus
• Growth cones migrate via environmental sensing using signals similar to migrating neural crest cells

Growth Cones and Microspikes

• Growth cones move via elongation and contraction of filopodia called microspikes
• Microspikes attach to the correct substrate to exert force, pulling the cell body forward

Axon Navigation

• Navigation of axons to targets depends on guidance molecules in the extracellular environment

Rho GTPases

• Rho GTPases (RhoA, Rac1, and Cdc42) are regulators of actin filament dynamics and thus drive movement

Axon Growth

• Pioneer nerve fibers go ahead as guides
• Pioneer neurons migrate when embryonic distances are short
• Some pioneer neurons die after follower neurons reach destinations

Specificity of Neuronal Connections

• Pathway Selection: axons travel a route toward a specific region for development
• Target Selection: axons recognize and bind to cell sets in a region to form stable connections
• Address Selection: initial pattern is refined such that each axon binds a small target subset based on neuronal activity

Axon Guidance

• Axonal growth cones are guided by cues from the extracellular matrix, transmembrane proteins and secreted protein
• Adherence to certain substances promotes growth, while others retract growth cones
• Growth cones prefer adhesive surfaces, so molecules like laminin help direct axons

Fasciculation

• Axons often use previously laid axons for growth, known as fasciculation
• Pioneers are an example of this
• Sensory neurons dependent on motor neuron axons are another example

Transmembrane and Secreted Protein Cues

• For axons, Transmembrane and secreted protein cues include ephrins, semaphorins, netrins, and slit proteins
• These same proteins also regulate neural crest cell migration

Semaphorins

• Ephrins, semaphorins, netrins, and Slit proteins promote attraction or repulsion, depending on receptor type that is present on the axon

Ephrins

• They are membrane-anchored or transmembrane proteins
• The Eph receptors recognize them

Semaphorins

• They are transmembrane and secreted proteins
• The neuropilin receptors recognize them
• In most cases, both protein types act via repulsion

Netrins

• Netrins are diffusible chemotactic cues for neuron guidance
• DCC and DSCAM receptors found in axon growth cones recognize netrin-1
• Attractive but can switch to repulsive mechanisms

Slit Proteins

• Slit proteins are diffusible and act in repulsion (chemorepulsion)
• Roundabout (Robo) is the receptor family for Slit
• Robo1/2 repulses neurons
• Downregulation of Robo1/2 allows commissural neurons to cross midline
• Robo3.1 promotes midline crossing

Neuronal Targets

• Once a neuron nears targets, it responds to chemotactic peptides like endothelins and neurotrophins
• Blood vessels secreting endothelins direct migration of neural crest (gut entry) cells and sympathetic axons having endothelin receptors
• Endothelins also work to constrict blood vessels

Neurotrophins

• They include NGF (nerve growth factor), BDNF (brain derived neurotrophic factor), CDNF (conserved dopamine neurotrophic factor), and neurotrophins 3 (NT3) and 4/5 (NT4/5)
• They travel short distances and can act as attractants or repulsive factors

Synapse Formation

• It occurs when an axon contacts its target (muscle cell or another neuron)
• It involved thickened membranes of both cells, secretion of β2-laminin, possibly stopping further neuronal growth

Neuronal Cell Death

• Neuronal cell death, apoptosis, happens a lot in the central and peripheral nervous system and in many cases, more than half die
• This happens after axons have successfully differentiated and extended to targets
• Neurotrophin supply is limited

Axon Growth and Neurotrophic Factors

• Loss of neurotrophic production in adults can lead to diseases
• Huntington’s disease is caused by the loss of Huntingtin protein, resulting in a lack of upregulation of BDNF
• Parkinson disease is caused by loss of midbrain dopaminergic neurons and the survival of these could be improved with drugs that might activate neurotrophic factors

Ectodermal Placodes

• They are thickenings of surface ectoderm and become rudiments of numerous organs
• Cranial placodes (sensory placodes) contain olfactory (nasal), auditory (ear), and lens (eye) placodes
• Non-sensory placodes make cutaneous structures (hair, teeth, feathers, and mammary and sweat glands)

Cranial Placodes

• Local, transient ectoderm thickenings in the head and neck between prospective neural tube and epidermis, which will become sense organs and cranial ganglia
• The cranial placodes, along with the neural crest, mostly generate peripheral neurons which are responsible for smell, taste, hearing, balance, blood pressure, touch, pain temperature
• The lens placodes don’t produce neurons

Anterior Cranial Placodes

• The adenohypophyseal placode gives rise to the anterior lobe of the pituitary gland and it does not generate sensory neurons
• The lens placode makes the eye lens and does not generate sensory neurons
• The olfactory placode produces sensory neurons for smell and other hormone-secreting neurons

Intermediate Cranial Placodes

• The trigeminal placode has ophthalmic and maxillomandibular sections
• It generates distal neurons of trigeminal ganglia, which support the sensations of touch, temperature, and pain

Posterior Cranial Placodes

• The otic placode (inner ear) generates neurons that transmit sound and balance
• The epibranchial placodes produce geniculate, petrosal, and nodose placodes that innervate organs of the body

Pre-Placodal Region

• The placodal domain (pre-placodal region) and specific placode regions are specified by timing and placement of paracrine factor expression
• Wnt induction of BMP, succeeded by Wnt downregulation, selects the pre-pan-placodal field
• Later, FGF and Cerberus (which reduce Wnt and BMP), are active

Otic-Epibranchial Development

• Hearing and balance are accomplished by transforming mechanical information into electrical stimuli by the inner ear's sensory hair cells
• Sound waves are captured by the outer ear and conveyed to the tympanic ear drum
• Eardrum vibrations are amplified by middle ear bones and transferred as waves to cochlear fluid

Mammalian Cochlea

• The cochlea has three chambers
• The middle fluid-filled chamber has the Organ of Corti housing sensory hair cells that transform fluid movement into electronic signals
• A nearby epibranchial placode forms three cranial nerves: facial (VII), glossopharyngeal (IX), and Vagus (X)
• Together they control facial expressions, sense of taste/speech/swallowing, heartbeat, sweating, and peristalsis

Otic-Epibranchial Placode Induction

• Fgf from the head mesoderm first specifies the posterior pre-placodal region
• Fgf then reinforces this process from pharyngeal endoderm and neural plate
• Wnt signaling from neural plate advances otic identity, repressing epibranchial fate
• BMP from pharyngeal endoderm then promotes

Otic Vesicle Formation

• Otic vesicle is formed by 1st forming an indentation of the otic placode, forming an otic put and then an otic cup
• It pinches to make the otic vesicle, like the neural tube

Ganglia

• Sensory neurons formed by placodes (by otic and epibranchial placodes) generated from delamination of neuroblast cells
• Otic neuroblast cells separate into the cochleovestibular ganglion, which makes the major neural connection between the brain and inner ear

Neuroblasts

• Neuroblasts from epibranchial placodes migrate dorsally being helped by guidance cues forming neural crest cells

Optic Development

• The lens placode constructs the lens of the eye
• It is also unlike other sensory placodes
• Prechordal plate mesoderm and head endoderm contact head ectoderm, activating Pax6 in ectoderm

Optic Vesicles

• They form later from bulges of the forebrain, namely the diencephalon
• The optic vesicle induces the head ectoderm to construct the lens placode

Optic Cup

• The optic vesicle then bends to form the two layered optic cup which pulls the developing and invaginating lens into the embryo
• The outer later (back) of the optic cup forms the pigmented retina
• The inner cells proliferate and differentiate into photoreceptors and other neurons
• The retinal ganglion cells of the neural retina send electrical impulses to brain
• Axons converge towards base and generate optic nerve

Eye Development

• The first step in eye field construction comes down to activation of the transcription factor Otx2 in the anterior neural tube, the eye field specification
• This is related to expression of ET, which activates Rx (retinal homeobox), and also specifies the retina
• Rx then activates Pax6
• Major expression by Pax6 specifies the eye field in the anterior neural place
• Sonic hedgehog (secreted by the prechordal plate) splits the eye field into two and suppresses Pax6 in the center of the neural tube
• Excess sonic hedgehog results in loss of eyes in cave fish