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Neuroscience > Unit 1 - Early Development of Nervous System > Flashcards

Unit 1 - Early Development of Nervous System Flashcards

1
Q

gastrulation

  • when it happens
  • what happens
  • what it defines
A

day 7 post fertilization (most important event that defines you)

  • invagination at specific site in blastula leads to 3 different tissue layers
  • defines midline, anterior-posterior, and dorsal-ventral axes of embryo
  • by the end of gastrulation, the midline of embryo is defined by formation of notochord and inducing formation of neural ectoderm in early neurulation
  • -critical for formation of all tissue including CNS
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2
Q

early neurulation

A

day 18 post fertilization; very first event in neurogenesis

  • coincident with gastrulation signaling events, neural ectoderm is induced
  • neural ectoderm are neural precursor cells
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3
Q

the fate of ectoderm and neural induction

A

BMP made by surrounding tissue, and push ectoderm towards epidermal state
-inhibited by notochord factors (chordin, noggin) and other Nodal and Wnt inhibitors, and block BMP signaling in ectodermal cells overlying notochord (midline cells), causing them to take a neural fate

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4
Q

what does BMP stand for?

A

bone morphogenic proteins; subclass of transforming growth factor beta family

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5
Q

what is the “default fate” of ectoderm?

A

neural fate due to absence of signaling cells (since the noggin/chordin blocks it; this is what happens in isolated ectodermal precursor cells)

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6
Q

BMP signaling

A

BMP bind to receptor serine kinases and a SMAD complex transported to nucleus to mediate transcription

  • BMP activity drives formation of epidermis
  • chordin, noggin, and follistatin produced in notochord inhibit BMP signaling and lead to neural induction
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7
Q

other than the inhibitors, what else induces neural stem cell formation?

A

stimulation of retinoic acid (RA), fibroblast growth factor (FGF), and insulin-like growth factor (IGF)

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8
Q

what is the complexity of neural induction?

A

coordination of multiple signaling pathways are required for neural induction

  • FGF signaling precedes BMP inhibition during neural induction
  • FGF stimulation increases production of noggin to inhibit BMP
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9
Q

late neurolation (after neural induction)

A

happens from day 20 to day 24

  • D20: lateral margins of neural plate fold inward to form neural tube very rapidly
  • -cells that make up tube are neural stem cells
  • D22: as neural plate closes to form neural tube, the neural crest pinches off and the roof plate forms
  • -neural tube closes from middle both anteriorly and posteriorly
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10
Q

what is neural tube closer sensitive to?

A

nutrition and environmental toxins

-folic acid is particularly important, along with other B-complex vitamins, although the mechanism is unknown

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11
Q

spina bifida

A

most common neural tube closure defect

  • 1:1000 worldwide, 3.5:10,000 US
  • due to lack of folic acid somehow causing failure of posterior end of neural tube to close
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12
Q

anencephaly and holoprosencephaly

A

1: 68,0000 and 1:16,000 respectively
- represents failure of anterior neural tube to close
- lack prosenchalon (forebrain) due to disrupted Shh signaling
- typically deadly

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13
Q

what happens to the neural crest after it pinches off?

A

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

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14
Q

dorsal ventral patterning and how it makes such dorsal-ventral axis diversity

A

makes cells in one area different from cells in another area

  • ventral signal (motor) is secreted Sonic Hedgehog (Shh)
  • dorsal signal (sensory) is secreted TGF-B (mainly BMP)
  • more complex combinations of signaling through convergence of signaling pathways contribute to remarkable neuronal diversity along D/V axis involving FGF and RA signaling
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15
Q

what does high sonic hedgehog expression do and where is it?

A

highly expressed only in the notochord and roof plate

-absence in the roof plate produces dorsal-ventral polarity

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16
Q

Shh signaling

A

in the ventral neural tube, Shh binds to Patched (PTC) and relieves the PTC-dependent inhibition of Smoothened (SMO)

  • SMO activates the Gli class of zinc finger transcription factors
  • Gli induces transcription and leads to a ventral (motor neuron) cell fates
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17
Q

developmental defects in Shh patterning and what this tells us about Shh regulation

A
  • absence of Shh prevents forebrain formation, and dorsal-ventral polarity is disrupted (lethal)
  • disruptions in pathway can cause cancers like medulloblastomas and basal cell carcinoma, along with polarity of the entire head (cyclopia)

thus Shh regulates both polarity and proliferation

18
Q

cyclopamine

A

Shh antagonist that causes cyclopic sheep (in a plant they ate)

19
Q

development of dorsal-ventral polarity in the spinal cord

A

like neural induction, the precise pattern of different neuronal subtypes requires convergence of a number of different signaling cascades

  • roofplate: TGF-beta family BMPs, dorsalin, retinoic acid, noggin
  • somite: BMPs
  • floorplate: Shh, retinoic acid, noggin, chordin
20
Q

anterior-posterior patterning and what they lead to

A

overlaps with neural induction and gastrulation, and leads to:

  • spinal cord
  • rhomboencephalon (metencephalon future pons and myelencephalon future medulla)
  • mesencephalon-future midbrain
  • proencephalon (diencephalon future thalamus and retina, and telencephalon future forebrain)
21
Q

A/P patterning below midbrain (posterior CNS) depends on what kind of genes?

A

Hox (homeotic) genes originally found in flies

  • specific segment identify along A/P axis
  • proteins encoded by these genes are powerful transcriptional activators and repressors that turn on/off 1000s of other genes
  • the key to metazoan bodyplans
  • involved in defining segmental differences in spinal cord, medulla, and pons
  • in vertebrates, each segment involves combos 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
22
Q

where is there no Hox code?

A

proenscephalon and mesencephalon, so use EMX1, EMX2, OTX1, FGFs, and WNTs

23
Q

what do OTX2 knockouts do?

A

show complete loss of anterior polarity

-knockout embryos completely lack forebrain neural structures

24
Q

what regulates nervous system expansion?

A

coordination of symmetrical (divides into 2 of the same thing) and asymmetrical (2 different things) proliferation

25
Q

what is required to organize distinct cell types

A

cell migration

26
Q

ventricular zone

A

thin strip of cells surrounding 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

27
Q

what is the choroid plexus?

A

makes the CSF

28
Q

symmetric cell divisions

A

early in development, neural stem cells divide symmetrically, giving rise to 2 daughter cells that are both pluripotent neural stem cells capable of self-renewal

  • this increases the size of the ventricular zone, which increases the size of the brain
  • thickness of ventricular zone is constant, so increased NSCs expands ventricular zone laterally

-later in development (after asymmetrical), NSCs again divide symmetrically, but give rise to 2 neural precursors, so NSCs disappear

29
Q

asymmetric cell divisions

A

as development proceeds, NSCs divide asymmetrically and give rise to one NSC and one neural precursor
-neural progenitor will give rise to neurons and glia

30
Q

how do precursor cells divide?

A

they can divide symmetrically and asymmetrically

31
Q

which comes first: neurogenesis or gliogenesis?

A

neurogenesis precedes gliogenesis

32
Q

molecular mechanisms regulating neural cell differentiation

A

number of NSCs, progenitors, neurons, and glia need to be tightly controlled, as does the timing of their generation
-one of the major signaling pathways that controls this is Notch, and the proneural basic-helix-loop-helix (bHLH) transcription factors

33
Q

how do Notch and proneural bHLH transcription factors control neural progenitor differentiation?

A
  1. notch signaling through Delta requires cell-cell contact
    - at low/moderate levels of Notch stimulation through Delta, intracellular domain of Notch (NICD) is cleaved and goes to the nucleus to activate bHLH genes
    - ultimately through feed-forward circuit, this leads to high expression of proneural bHLH pritens, and cell is primed to differentiate into a neuron
  2. bHLH activation also upregulates Delta on these cells
    - thus in surrounding cells, Notch gets hyper-activated, which shuts off proneural bHLH genes and keeps them in pluripotent NSC state
    - very precise mechanism to control number of cells that differentiate into neural progenitors
34
Q

when does gliogenesis start?

A

after the peak of neurogenesis (astrogliosis –> oligodendrogiosis)

  • astrogliogenesis is Notch dependent, but inhibited by bHLH genes
  • oligodendrogiosis is Olig1/2 and Hkx2.1 dependent, but inhibited by bHLH genes
  • impact of signaling pathways depend on a “state” of a cell (which specific receptors and pathways are active in those cells)
35
Q

how long does neurogenesis last?

A

starts very early in human development, and in most regions is finished by middle of the second trimester (19th week)

  • basic shape of brain is fully formed at birth, and vast majority of neurons are already generated
  • -it’s smaller to fit through birth canal, but increases due to gliogenesis et al
36
Q

when the majority of gliogenesis happens?

A

after birth in humans

-almost no myelination in human at birth, and continues to increase to about 20 years old

37
Q

when is primary neurulation complete?

A

within first 3 weeks; defects in this time are usually deadly

  • expansion of neural precursors and neuronal development begins coincident with and immediately thereafter, and is very rapid
  • most neurons in cerebral cortex are made between first and fourth month of pregnancy
  • extremely sensitive to nutrition and environmental toxins at this time
38
Q

general effects of alcohol and drugs on brain development

A

alcohol: smaller, not well folded
drugs: decrease in size of gray matter in cortex and caudate

39
Q

neurogenesis and migration in cerebral cortex

A

cortex forms in an inside-to-outside manner

  • layers closest to ventricular zone form first while the ones further away from the ventricular zone form last in very orderly pattern
  • first born cells migrate from ventricular zone to pial surface, and subsequent cells take the same radial migration route, thus migrate about previously born cells
40
Q

radial migration regulated cortical layer formation

A

radial migration of neurons depends on radial glia

  • radial glia in ventricular zone have process that extends from ventricular zone all the way to pial surface
  • postmitotic cells called neuroblasts (become neurons) migrate along radial glial fibers until they reach the pial surface, at which point they detach from the fiber so cortex is in inside-out fashion
  • radial glia are neural stem cells of developing nervous system, and give rise to neurons plus provide scaffolding on which they can migrate to appropriate destination
41
Q

what regulates radial migration? what happens if there is a mutation?

A

Reelin; if there is a mutation, then there is “outside-in” layering such that first born cells can’t get past the older cells

42
Q

how do interneurons migrate?

A

tangentially over long distances in cortical development, since interneurons are derived from a different location (medial and lateral ganglionic eminences) thus cannot migrate radially
-mediated by distinct mechanisms and involves DLX1/2 and Mash1 transcription factors

Neuroscience (39 decks)

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