Early Development of the Nervous System

Question 1

gastrulation

Answer 1

• invagination at specific site in the blastula leads to the formation of three different tissue layers
• gastrulation defines the midline, anterior-posterior and dorsal-ventral axes of the embryo
• by the end of gastrulation the midline of the embryo is defined
• defined by formation of the notochord
• critical for formation of all tissue including CNS

Question 2

early neurulation

Answer 2

• coincident with gatrulation signaling events, neural ectoderm is induced
• notochord formation is central to gastrulation by defining the midline of the embryo and inducing the formation of neural ectoderm
• very first event in neurogenesis
• neural ectoderm are the neural precursor cells

Question 3

neural induction

Answer 3

• bone morphogenic proteisn (BMPs)-subclass of the TGFb family are produced by surrounding tissue
• BMPs push ectoderm towards epidermal state
• Noggin and Chordin inhibit BMP and are produced by the notochord. makes neuroectoderm cells
• neural fate is default and inhibiting BMPs allow nueroectoderm to form

Question 4

BMP signaling

Answer 4

• BMPs bind to receptor serine kinases and a SMAD complex that is transported to the nucleus to mediate transcription
• drives formation of epidermis
• chordin, noggin, and follistatin inhibit BMP and come from notochord

Question 5

neural induction 2

Answer 5

• neural inducers that act as inhibitors of BMPs, nodal and Wnt signaling promotes ES (stem cell) cell differentiation to committed neural stem cells
• retinoic acid, FGF, and IGF induce neural stem cell formation

Question 6

coordination of multiple signaling pathways

Answer 6

• FGF signaling precedes BMP inhibition during neural induction (on before inhibition)
• FGF stimulation increases production of noggin
• complexity

Question 7

neurulation

Answer 7

• after neural induction the lateral margins of the neural plate fold inward to form the neural tube
• proceeds very rapidly
• cells that make up the neural tube are neural stem cells
• floor plate and neural crest
• as neural plate closes, neural crest pinches off to neural crest cells and roof of plate forms
• closes in middle first and then zippers out
• neural crest closure is sensitive to nutrition and toxins
• folic acid and b vitamins

Question 8

neural tube closure defects

Answer 8

• spina bifida-most common NTD 1 in 1000 worldwide, 3.5/10,000-failure of posterior end of the neural tube to close
• anencephaly and holoprosencephaly 1/68,000 and 1/16,000
• failure of anterior neural tube to close
• lack prosencephalon
• typically deadly

Question 9

neural crest

Answer 9

• as tube closes neural crest pinches off
• gives rise to:
• cranial neural crest-cranial ganglia, bones, and cart in face and head
• trunk neural crest-DRGs, sympathetic ganglia, adrenal medulla, menaloncytes
• vagal and sacral neural crest-PNS ganglia
• cardiac neural crest-cartilage, melanocytes, neurons of the pharyngeal arches, regions of the heart

Question 10

dorsal ventral patterning

Answer 10

• makes cells in one area different from cells in another area
• ventral-motor-sonic hedgehog-lots in foot plate and notochord
• dorsal-sensory-TGFbetas- in roof plate
• more complex combinations of signaling through convergence of signaling pathways contribute to the remarkable neuronal diversity alons the D/V axis primarily involving FGF and RA

Question 11

SHH signaling

Answer 11

• in ventral neural tube SHH binds to patched and relieves the PTC dependent inhibition of smoothened
• SMO activates the Gli class of zinc finger transcription factors
• Gli induces transcription and leads to a ventral cell fates
• absence leads to no forebrain and DV polarity disrupted
• disruptions can cause cancer such as medulloblastomas and basal cell carcinoma
• polarity of entire head messed up
• sheep eating cyclopamine

Question 12

dorsal-ventral polarity

Answer 12

• precise pattern of different neuronal subtypes requires the convergence of a number of signaling cascades
• RA and FGF play key roles

Question 13

RA and FGF

Answer 13

-affect transcription

Question 14

brain polarity

Answer 14

• number of disorders are problems with polarity
• understanding molecular mechanisms that control cell fate decisions may in the future harness embryonic stem cells and neural stem cells for therapeutic purposes

Question 15

anterior posterior patterning

Answer 15

• overlaps with neural induction
• leads to spinal cord
• rhombencephalon-metencephalon-future pons, myelencephalon-future medulla
• mesencephalon-future midbrain
• prosencephalon-diencephalon-future thalamus and retina, telencephalon- future forebrain

Question 16

Hox genes

Answer 16

• homeotic genes
• specific segment identiry along A/P axis
• proteins are powerful TFs
• key to metazoan body plans
• define segmental differences in spinal cord, medulla, pons
• in vertebrates each segment involves combinations of multiple Hox genes expressed in complex patterns
• work through repressing and enhancing each other to create unique patterns of gene expression in each segment
• no Hox for prosencephalon and mesencephalon

Question 17

cell proliferation and migration

Answer 17

• coordination of symmetrical and asymmetrical proliferation regulates nervous system expansion
• cell migration is required to organize distinct cell types into functional units

Question 18

ventricular zone

Answer 18

• thin strip of cells surrounding the CSF filled ventricles
• neural stem cells and neural progenitor cells divide and differentiate in this zone to give rise to all the cells in the CNS

Question 19

layers in brain

Answer 19

• ventricular layer
• subventricular layer
• intermediate zone
• cortical plate
• marginal layer

Question 20

symmetric and asymmetric cell divisions

Answer 20

• early they divide symmetrically giving rise to 2 daughter cells, both pluripotent neural stem cells
• increases the size of the ventricular zone, increases brain size
• thickness of ventricular zone stays relatively constant so increased NSCs expand ventricular zone laterally
• NSCs then divide asymmetrically and give rise to one NSC and one neural precursor-progenitors that give rise to neurons and glia
• late in development NSCs divide symmetrically again but give rise to two neural precursors and therefore NSCs disappear
• precursor cells can also divide symmetrically and asymmetrically

Question 21

time course

Answer 21

• neurogenesis first
• then gliogenesis
• gliogenesis occurs after birth
• brain gets bigger because more glial cells, myelination, connections

Question 22

mechanisms regulating neural cell differentiation

Answer 22

• number of NSCs, progenitors, neurons, and glia needs to be tightly controlled as does the timing of their generation
• notch pathway controls
• proneural basic helix loop helix TFs

Question 23

notch pathway

Answer 23

• notch signaling through delta requires cell-cell contact
• at low/moderate levels of notch stimulation through delta (low delta, less notch), intracellular domain of notch is cleaved and goes to nucleus to activate bHLH genes
• through feed forward leeds to high expression of proneural bHLH proteins and cell differentiates into a neuron
• bHLH activation upregulates delta
• increasing delta in this cell increases notch in surrounding cells, and they don’t differentiate into neurons because bHLH is turned off
• very precise

Question 24

gliogenesis

Answer 24

• neurogenesis, astrogliogenesis, oligodendrogenesis
• signaling pathways reused
• astrogliogenesis activated by notch and inhibited by bHLH
• ilogodendrocyte induced by olig1/2 and inhibited by bHLH
• impact of signaling pathways depend on the state of a cell

Question 25

timline

Answer 25

• neurogenesis early in humans
• most regions finished by middle of second trimester
• neocortex in which neurons are still being produced in a rodent at birth, finished by 19th week in humans
• timing of gliogenesis not well established and happens mostly after birth in humans
• not much myelination in the human at birth and increases to about 20 years old

Question 26

neural development and exposure to drugs and toxins

Answer 26

• primary neurulation complete in about first 3 weeks, defects during this time are often deadly
• expansion of neural precursors and neuronal development begins coincidently and immediately thereafter and is very rapid
• most neurons in the cerebral cortex are produced between the first and 4th month of pregnancy
• brain is extremely sensitive to nutrition and environmental toxins
• vitamin a, drugs of abuse
• exposure at any time can lead to neural defects

Question 27

neurogenesis and migration

Answer 27

• inject with radio labeled thymidine
• only labels cells in S phase
• cortex in monkeys formed in an inside to outside manner
• layers closest to the ventricular zone were first to form while the ones farther away formed last
• oldest ones were closer to ventricular zone

Question 28

radial migration

Answer 28

• inside out formation
• first born cells migrate from ventricular zone to the pial surface and subsequent cells take the same radial migration route and therefore migrate above previously born cells
• depends on radial glia
• radial glia in the ventricular zone have a process that extends from the ventricular zone all the way to the pial surface
• postmitotic cells called neuroblasts migrate along the radial glial fibers until they reach the pial surface, then detach
• radial glial cells are the neural stem cells of the developing nervous system

Question 29

radial glial cells

Answer 29

-give rise to neurons and provide scaffolding on which they can migrate from ventricular zone

Question 30

reelin

Answer 30

• regulates radial migration
• mutation in this causes backwards formation- youngest closes to VZ
• cause brain malformations
• projection neuron problems

Question 31

interneurons

Answer 31

• migrate tangentially over long distances
• derived from different location and migrate long distances
• derived from medial and lateral ganglionic eminences (MGE and LGE) and cannot use radial migration
• mediated by distinct mechanisms and involves DLX1 and 2 and Mash1

Question 32

migration in neural development

Answer 32

• both CNS and PNS built by immigrants

- migration is complicated and may in part reflect the need for different types of cells in the same circuit