Formation of the Nervous System

& Epidermis II

Differentiation of the Neural Tube

• Occurs simultaneously in three ways

– 1. Gross level - neural tube bulges and constricts to form chambers of the brain and spinal cord

– 2. Tissue level - the cell populations within the wall of the neural tube rearrange themselves to form the different functional regions of the CNS

– 3. Cellular level - neuroepithelial cells themselves differentiate into numerous types of nerve cells (neurons) and support cells (glial cells)

First Brain Regions

• Anterior most neural tube balloons into

– Forebrain (prosencephalon)

– Midbain (mesencephalon)

– Hindbrain (rhombencephalon)

• As the posterior end of the neural tube closes - optic vesicles are extending laterally from each side of the developing forebrain

Three Primary Vesicles

Prosencephalon

• Subdivided into:

– Anterior telencephalon - forms the cerebral hemispheres -higher functions, olfaction, memory storage(hippocampus), motor control & sensory processing

– More caudal diecephalon - forms thalamus (sensory relay) and hypothalamus (homeostasis control center)

Mesencephalon

• Does not become subdivided

• Optic lobes

• Tectum (sensory processing center)

• Fiber tracts (between anterior and posterior brain regions)

• Its lumen eventually becomes the cerebral aqueduct

Rhombencephalon

• Metencephalon

– Cerebellum - coordination & learning

– Pons - control of respiration

• Myelencephalon

– Medulla oblongata -(reflex centers) control of respiration, heart rate, blood pressure, vomiting & coughing etc.

Rhombencephalon

• Develops a segmental pattern that specifies the places where certain nerves originate

• Periodic swellings are called - rhombomeres - divide the rhombencephalon into smaller compartments

– Separate area where cell mixing occurs but never between rhombomeres

– Each will form ganglia - from these clusters of cells bodies axons will generate cranial nerves

Rapid Brain Expansion

• Fluid secretion puts positive pressure on the vesicles

• In chick - thirty-fold increase between day 3 and 5 of development

• If fluid pressure is experimentally removed - chick brain enlarges at a much slower rate - also contains fewer cells

Early Brain Vesicles and Adult Derivatives

Human Brain Development

Ventral Patterning of the Neural Tube

• Specification of the ventral neural tube - sonic hedgehog protein probably from the notochord

– Also retinoic acid from adjacent somites is involved

• Sonic hedgehog establishes a gradient - different levels of the protein - causes formation of different cell types

• Initially induces medial hinge cells to become the floor plate

• Transplanted notochord will induce second set of ventral floor plate neurons

Dorsal-Ventral Specification - Neural Tube

Chick Neural Tube

Notochord induction of the the Neural Tube

Dorsal Patterning of the Neural Tube

• Established by proteins of the TGF-b superfamily

• Epidermis establishes a secondary signaling center by inducing BMP4 expression in Roof plate cells of the neural tube

• This in turn induces a cascade of TGF- b proteins in adjacent cells

• Again different concentrations of TGF b proteins induce different transcription factors that give the various cells their different identities

Dorsal-Ventral Specification - Neural Tube

Architecture of the CNS

• Neurons of the brain are organized into layers and groups of cells called nuclei

• The early neural tube is composed of a germinal neuroepithelium - one cell layer thick - these are neural stem cells

• The nuclei of these cells are at different height - looks like several cell layers - but only one

• Nuclei move as they go thorough the cell cycle

• When a neuroepithelial cells divides vertically and not horizontally - it is born

• Cells located superficially are born later than those adjacent to the lumen

Nucleus Position and and The Cell Cycle

Spinal Cord and Medulla Organization

• New cells are formed by mitosis - migrate to form a second layer around the original neural tube

– Thicken to form germinal neuroepithelium - called intermediate zone (mantle)

– Germinal epithelium - now ventricular zone (later the ependyma)

– Mantle zone - neurons & glia

Spinal Cord and Medulla Organization

• Neurons make connection among themselves - send out axons - get cell-poor marginal zone

• Eventually glial cells cover these axons - whitish appearance

• Thus mantle zone (intermediate) with cells bodies called gray matter

• The axonal, marginal layer - called white matter (glial myelination)

Spinal Cord and Medulla Organization

• In spinal cord and medulla - basically the three layers just discussed through out development

• Sulcus limitans - develops and divides dorsal and ventral portions

Human Spinal Cord Development

Cerebellar & Cerebral Cortex Organizations

• Cerebellum adds new germinal zone - external germinal layer -near the outside

• Eventually these cells form a granule cell layer deeper in

• Purkinje cell - main output cell - large dendritic field (arbor) - 100,000 plus connections

• Neurons migrate out of the ventricular zone on the processes of glial cells

– Glial guidance

Glial Guidance of Neuron Migration

Cerebellar and Cerebral Differentiation

Cerebral Organization

• Two types of spatial organization

– Organized vertically into layers that interact with one another - like the cerebellum

– Also organized horizontally into over 40 regions - handle anatomically and functionally distinct processes

Cerebral Vertical Organization

• New layer - certain neuroblasts from the mantle zone migrate on glial processes through the white matter to form a new (2nd) zone of neurons at the outer surface of the brain

– Neocortex - Stratifies into 6 layers of cell bodies

– Adult form of these layers not complete until about age six

– Each layer is functionally different - inputting and outputting to different areas

Cerebellar and Cerebral Differentiation

Cerebral Organization & Stem Cells

• Cell fates are often fixed as they undergo their last division

• Neurons derived form the same stem cell may end up in different functional regions of the brain

– Most migrate radially on glial cell processes - but some migrate laterally from one functional region into another

• Appears that humans can continue to make neurons throughout life - but at a lower rate that in the fetus

Developing Neurons

• Soma - cell body of a neuron

• Dendrites - fine input processes of a neuron - typically do not extend far from the soma

• Axon - long distance communication process of a neuron - can be many feet in length

– Axon growth can occur at 56mm/hr

– Growth is led by a the growth cone a the tip of the growing process

• Growth cone movements via - pointed filipodia called microspikes

• Microspikes contain microfilaments

Developing Motor Neuron

Axon Growth Cones

Developing Neurons

• Most central and many peripheral neurons have myelin sheaths - these act to speed up conduction velocity of nerve impulses (action potentials)

• Centrally oligodendrocytes wrap several different axons forming the myelin sheath

• Peripherally schwann cell do this - however a given Schwann cell only wraps a single axon

• Synapses at specialized junctional areas where one neuron communicates with another

– Communication is typically by means of a chemical (neurotransmitter) released by an axon onto typically a dendrite, soma or even another axon

Myelination of Neurons

Development of the Vertebrate Eye

• The optic vesicles evaginate from the diencephalon

• When it meets the surface ectoderm it induces the formation of the lens placode - it then invaginates to form the lens

Development of the Vertebrate Eye

• Optic vesicles becomes the two walled optic cup - the two layers differentiate in different directions

– Cells of the outer layer become the pigmented retina

– Cells of the inner layer - glia, ganglion cells, interneurons and photoreceptors - neural retina

• Ganglion cell axons form the optic nerve when they leave the eye

Development of Vertebrate Eye

Development of the Vertebrate Eye

• Pax6 plays a major role in eye formation

• Down regulation of Pax6 by Sonic hedgehog in the center of the brain splits the eye-forming region of the brain in half

• If sonic hedgehog is not expressed a single median eye results

Brain Defects - No Sonic Hedgehog

Development of Human Retina

Lens and Cornea Differentiation

• Intraoccular fluid pressure - shapes cornea curvature -to focus light on the retina

– Lens vesicle induces ectoderm to form transparent cornea

• Differentiation of lens tissue into a transparent membrane

– Involves changes in cell structure and shape

– Synthesis of transparent - lens specific proteins - crystallins

Differentiation of Lens Cells

Origin of Epidermal Cells

• Cells covering the embryo after neurulation - from the presumptive epidermis

• Originally one cell layer thick but then become two layers thick

• Periderm - outer layer - temporary covering that is shed once the inner layer differentiates to from a true epidermis

• Basal layer (stratum germinativum) - inner layer - germinal epithelium that gives rise to all the cells of the epidermis

Origin of Epidermal Cells

• Basal layer divides and forms another layer- outer population of cells, the spinous layer

• Malpighian layer - spinous layer and basal layer

• Cells of the Malpighian layer divide to produce the granular layer - cells contain granules of kerratin

– These do not divide any further - differentiate into skin epidermal cells - keratinocytes

– Migrate outward to form the cornified layer (stratum corneum)

– Cells become flattened sacs of kerratin protein - nuclei pushed to one side

Layers of Human Epidermis

Origin of Epidermal Cells

• Epidermal stem cells of the Malpighian layer bound to the basal lamina by their integrin proteins

• As they become committed to differentiate - integrins are loss and the cells can migrate into the spinous layer

• This layer varies in thickness from 10 to 30 cells thick

Cutaneous Appendages

• Epidermis and dermis interact at specific sites to form sweat glands and cutaneous appendages, hairs, scales, or feathers

• In mammals hair follicle primordium or hair germ - forms as an aggregation of cells in the basal layer of the epidermis

– Directed by underlying fibroblast cells of the dermis

– These cells elongate and sink into the dermis - dermal cells now form a small node - dermal papilla

– Pushes up on basal cells - stimulates them to divide more rapidly

– Hair shaft, sebaceous gland swelling and bulb containing pluirpotent hair follicle stem cells (for hair replacement)

Development of Human Hair Follicles