Chapter 10: Late Development CNS and Epidermis

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Chapter 10: Late Development CNS and Epidermis
2014-03-27 00:58:18

Developmental Biology
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  1. Neurulation
    • •Neurulation- Formation of rudimentary CNS
    • •Neural Ectoderm: dorsal ectoderm --> CNS
    • •Neural plate – Embryonic region of neural differentiation
    • •Neurula – embryonic stage undergoing neurulation
    • •Neuroblasts - precursor cells go through competence, specification, commitment and differentiation
  2. Formation of Neural tube
    • •Primary Neurulation: Cells surrounding neural plate direct the neurogenic ectoderm to proliferate, invaginate and pinch off from surface to form a hollow tube
    • •Secondary Neurulation: Actual formation of neural tube from solid cells including cavitation
    • •Actual mode of construction of neural tube varies among species
    •  -Even among the same species, different parts of neural tube (head, trunk and caudal regions) are constructed differently – based on their relationship with overlying ectoderm
  3. Primary Neurulation
    • 3 Sets of cells
    • 1.Externally positioned cells --> epidermis, skin
    • 2. Neural crest cells - region that connects the neural tube and epidermis --> migrates elsewhere and generate peripheral neurons, glial cells, pigment cells of skin
    • 3. Internally positioned cells --> brain and spinal cord
  4. PrimaryNeurulation– The Process
    • Neural plate – thickening of edges 
    • --> move upwards to form neural folds
    • --> formation of U-shaped neural groove 
    • --> migration of neural folds towards midline 
    • --> fusion of edges, neural tube beneath ectoderm

    Cells at dorsal-most portion of neural  tube become neural crest cells

    • Divided into 4 stages:
    • - formation of neural plate
    • - shaping of the neural plate
    • - bending of the neural plate
    • - closure of neural tube
  5. Formation of Neural plate
    Process begins when underlying dorsal mesoderm signals the ectodermal cells above to elongate into columnar neural plate (along anterior-posterior axis)
  6. shaping of Neural plate
    • -Neural plate is shaped by intrinsic movements 
    • - These events occur even if the tissues are separated 
    •      - isolated neural plate converge and extend, but   cannot roll up 
    •      - isolated border region --> forms small neural fold
  7. Bendingof Neural Plate

    Hinge region – epidermal (medial hinge point or MHP) cells adhere to lateral edge of neural plate and move them toward midline 

    MHP cells become anchored to notochord beneath and forms the hinge --> formation of furrow at dorsal midline

    Other hinges: Dorsolateral hinge points (DLHPs) – anchored to surface ectoderm of neural folds

    DLHPs increase their height --> become wedge shaped

    Surface ectoderm pushes toward midline --> MHP cells decrease their height --> wedge shaped neural groove

    Role of cytoskeleton in wedging - microtubules and and microfilaments - In Xenopus actin binding-protein Shroom is critical in initiating wedging

  8. Closure of the neural tube
    Neural tube closes as paired neural folds are brought together at dorsal midline --> folds adhere to each other --> cells from each fold merge

    Cells at the junction become neural crest cells

    Closure does not occur simultaneously throughout

    When cephalic region is in neurulation

    Caudal region is still in gastrulation
  9. Role of Adhesion Proteins in Neurulation
    N-cadherin and N-CAM are expressed in neural plate

    E-cadherin is expressed in presumptive ectoderm

    During neural tube closure N-cadherin producing cells on opposite horns come together and fuse

    Experimental: injection of N-cadherin into  presumptive epidermis on one side  failure to close neural tube
  10. Neurulationin Chick Embryo
    Regionalization of neural tube occurs 

    Cephalic region --> series of swellings --> parts of brain Caudal region --> simple tube

    Neurulation – zips up
  11. Neurulation in Human Embryo
    On 22nd day both anterior and posterior neuropores are open to amniotic fluid

    • On 23rd day, anterior neuropore begins to close --> gets separated from surface
    • ectoderm

    Pax3, Sonic hedgehog and openbrain proteins play a role in the closure of neuropores

  12. Neural Tube Defects
    In mammals neural tube closure is initiated at several places along A-P axis

    Defects or delays in closure --> neural tube defects (1 in 1000 live births).

    Folic acid intake during pregnancy reduces neural tube defects

    Cranio-ra-chis-chi-sis: failure to close entire neural tube

    Ancephalopathy: Failure to close anterior neural tube regions --> forebrain is exposed to amniotic fluid --> disintegrates --> failure to form skull

    Spina bifida: Failure to close  the posterior region by 27th day --> subsequent rupture of posterior neuropore thereafter > exposure of spinal cord
  13. Folic acid prevents Neural tube defects
    Human neural tube closer  - as a result of interaction between Pax3, shh, openbrain genes as well as dietary factors like cholesterol and folate

    Over 50% neural tube defects could be prevented with folate supplementation (0.4 mg/day)

    Mothers in low socioecomic group --> higher incidence of NT defect babies, despite taking folate 

    - fungal contaminated crops produce a teratogen (fumonisin) --> possibly responsible for NT defects
  14. Expression of Folate receptor
    Folate receptor protein is expressed at the dorsal-most regions of neural pore prior to closure 

    - mice with mutations in folate receptor -->   Neural tube defects
  15. Secondary Neurulation
    Formation of neural tube from solid cord of cells that sinks into embryo --> hollow out to form a tubeExtent of usage of secondary neurulation varies  

    - Fishes – neurulation is exclusively secondary 

    -Frogs – caudal neural tube by secondary – instead of involuting, the caudal hinge grows ventrally à caudal notochord
  16. Differentiation of Neural tube
    Gross anatomical level – neural tube and its lumen bulge and constrict to form chambers of brain and spinal cord

    Tissue level - cell populations within the wall rearrange to form functional regions of brain and spinal cord

    Cellular level – neuroepithelial cells differentiate to form neurons and glial cells
  17. Differentiation of Brain lobes

    • Differentiation at Anatomical level:
    • 3 primary Vesicles --> 5 secondary Vesicles

    Forebrain (Prosencephalon) subdivides into  1. Telencephalon --> forms cerebral   hemispheres 

    2. Diencephalon --> thalamus and hypothalamus

    Midbrain (Mesencephalon) (3. secondary vesicles)

    Hind brain (Rhombencephalon) 

    4.)Metencephalon -->Cerebellum and Pons 

    5.)Myelencephalon --> medulla oblongata
  18. Dorsal-Ventral Patterning of Neural Tube
    Inflation of lumen of neural tube: Secretion of Na+/K+ ATPase --> osmotic gradient --> filling of water in the ventricle

    Neural tube is polarized along D-V axis

    Dorsal region – spinal neurons receive input from sensory neurons

    Ventral region – Place for motor neurons

    Middle region – internurons relay information between dorsal and ventral neurons

    Polarity is induced by signals from its immediate environment
  19. Dorsal- Ventral Patterning signals

    Specification comes from surrounding tissues

    Ventral Notochord -->  Sonic hedgehog protein (Shh) --> induces medial hinge cells to become floor plate  

         -->forms gradient of Shh (V-->D)

    • Dorsal region --> gradient of TGF-b   
    •      --> roof plate  
    •      --> dorsal neurons

  20. Model for Shh Morphogenic Gradient
    • At t0- t1: Shh from notochord induce Gli in the floor plate cells.

    Gli induces Olig2 -->inhibit Nkx2,2 and Pax6

    As Shh increase in most ventral cells --> Nkx2,2 is activated and Olig2 is suppressed.

    Shh and Nkx2,2 facilitated the formation of ventral.
  21. Differentiation of Neurons
    Human brain consists of > 100 billion neurons and make > 10 trillion synapses

    Neuroepithelial cells give rise to 3 cell types, differentiation largely dependent on environment

    1.Ventricular (ependymal) cells  - form remain components of neural tube --> secrete CSF

    2.Precursors of Neurons --> conduct electric potential

    3.Precursors of Glial cells --> aid in construction of nervous system, insulate neurons

    Neuron - Cell body, dendrites and axons

    Formation of axons is a major challenge
  22. Outgrowth Theory – Axon growth cone
    •Growth cone ‘feels” its way along the substrate, moves by elongation and contraction of filopodia called microspikes

    •Each microspike samples the microenvironment --> sends signals back to soma --> differentiate
  23. Unique Development of Human brain

    (Human brain development is plastic - work in progress, 5 features distinguishes from other primates)
    1.Retention of fetal neuronal growth rate after birth - unlike other primates, human brain continues to grow upto 2 years at the same rate 

    •       - neuronally speaking “premature birth”   
    •  2.) Genes for neuronal growth 
    •       - positive selection of ASPM gene after the divergence of humans from chimps

    • 3. High transcriptional activity 
    • - Human and Chimps are 99% similar genomically - but morphological and behavior differences are enormous 
    • - human brains produce five times as much mRNA as chimp brains

    • 4. Speech, language and FOXP2 gene 
    • - spoken language is unique to humans - fine-tuning of larynx (voice box) 
    • - individuals with heterozygous mutations in FOXP2 locus - problems with language and articulation 
    • - FOXP2 is extremely conserved in mammals, humans have unique form of this gene 
    • - in mouse it is expressed in lung but the human form is expressed in brain regions assigned to speech coordination

    • 5. Continued maturation of human brain 
    • - human brain keeps developing until around puberty. 
    • - soon after puberty growth ceases and pruning occurs --> correlates with slowing learning of new language
  24. Adult Neural Stem Cells
    Until recently it was believed once nervous system was mature, no neurons are “born”

    Recent labeling techniques revealed thousands are neurons are made each day in adult brains

    Evidence of existence of neural stem cells in adults is established for olfactory epithelium and hippocampus, but in cortex is controversial

    Cultured neuronal stem cells to regenerate or repair parts of brain has enormous therapeutic potential
  25. Development of Sense Organs
    • Sense organs develop by the interaction of neural tube with cranial ectoderm
    • Olfactory Placode – Nose;
    • Otic Placode – Ear;
    • Lens Placode --> lens --> Eye
  26. Inductive interactions - Eye development
  27. Separation of Eye Fields - Cyclopia
    Separation of two bilateral eye fields depends on the secretion of Shh

    Mutations of Shh or failure to process Shh to active (cholesterol-mediated mechanism) leads to failure to separate the eye fields --> cyclopia (single eye below the nose)

    Veratrum californicum interferes with cholesterol biosynthetic enzymes

    Pregnant cows eating V. californicum --> calves with cyclopia
    • •Mexican tetra fish Astyanx mecicanus 
    • - Surface-dwelling populations – eyes 
    • - Cave-dwelling populations – blind

    Too much of shh is synthesized in precordal plate of cave-dwelling fish --> Pax6 suppression --> no eye
  28. Epidermis– Origin of Cutaneous Structures
    Cells covering embryo form the presumptive epidermis

    Initially single cell layer thick --> two-layered

    Inner basal layer (stratum germinativum) is the germinal epithelium --> Cells of epidermis --> spinous layer

    Basal layer + spinous layer = Malpighian layer

    Malpighian layer --> granular layer (keratin granules)

    Keratinocytes from cornified layer (stratum corneum)
  29. Cutaneous Appendages

    • Epidermis and dermis -->  sweat gland and cutaneous appendages 
    • - hairs, scales, feathers

    Hair follicle primordium is formed by the aggregation of cells in basal layer

    Basal cell elongates --> sinks into dermis --> Ingression of epidermal cells forming dermal papilla (node)

    Dermal papilla stimulates basal cells --> keratinized hair shaft

    Melanoblast ingress --> transfer of pigments to the hair
  30. Stem cells
    • 3 types of stem cells in the bulge 
    • - hair follicular stem cells 
    • - melanocyte stem cells 
    • - epithelial stem cells

    Melanocyte stem cells --> pigment cells

    Follicular and Epithelial stem cells --> hair shaft

    Male pattern baldness is due to immune system attacking the hair follicle