Early Development of the Nervous System Flashcards
1
Q
gastrulation
A
- 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
2
Q
early neurulation
A
- 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
3
Q
neural induction
A
- 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
4
Q
BMP signaling
A
- 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
5
Q
neural induction 2
A
- 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
6
Q
coordination of multiple signaling pathways
A
- FGF signaling precedes BMP inhibition during neural induction (on before inhibition)
- FGF stimulation increases production of noggin
- complexity
7
Q
neurulation
A
- 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
8
Q
neural tube closure defects
A
- 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
9
Q
neural crest
A
- 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
10
Q
dorsal ventral patterning
A
- 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
11
Q
SHH signaling
A
- 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
12
Q
dorsal-ventral polarity
A
- precise pattern of different neuronal subtypes requires the convergence of a number of signaling cascades
- RA and FGF play key roles
13
Q
RA and FGF
A
-affect transcription
14
Q
brain polarity
A
- 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
15
Q
anterior posterior patterning
A
- 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
16
Q
Hox genes
A
- 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
17
Q
cell proliferation and migration
A
- coordination of symmetrical and asymmetrical proliferation regulates nervous system expansion
- cell migration is required to organize distinct cell types into functional units
18
Q
ventricular zone
A
- 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
19
Q
layers in brain
A
- ventricular layer
- subventricular layer
- intermediate zone
- cortical plate
- marginal layer
20
Q
symmetric and asymmetric cell divisions
A
- 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
21
Q
time course
A
- neurogenesis first
- then gliogenesis
- gliogenesis occurs after birth
- brain gets bigger because more glial cells, myelination, connections
22
Q
mechanisms regulating neural cell differentiation
A
- 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
23
Q
notch pathway
A
- 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
24
Q
gliogenesis
A
- 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
25
Q
timline
A
- 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
26
Q
neural development and exposure to drugs and toxins
A
- 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
27
Q
neurogenesis and migration
A
- 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
28
Q
radial migration
A
- 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
29
Q
radial glial cells
A
-give rise to neurons and provide scaffolding on which they can migrate from ventricular zone
30
Q
reelin
A
- regulates radial migration
- mutation in this causes backwards formation- youngest closes to VZ
- cause brain malformations
- projection neuron problems
31
Q
interneurons
A
- 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
32
Q
migration in neural development
A
- 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
