Unit 1 - Early Development of Nervous System Flashcards
gastrulation
- when it happens
- what happens
- what it defines
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
early neurulation
day 18 post fertilization; very first event in neurogenesis
- coincident with gastrulation signaling events, neural ectoderm is induced
- neural ectoderm are neural precursor cells
the fate of ectoderm and neural induction
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
what does BMP stand for?
bone morphogenic proteins; subclass of transforming growth factor beta family
what is the “default fate” of ectoderm?
neural fate due to absence of signaling cells (since the noggin/chordin blocks it; this is what happens in isolated ectodermal precursor cells)
BMP signaling
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
other than the inhibitors, what else induces neural stem cell formation?
stimulation of retinoic acid (RA), fibroblast growth factor (FGF), and insulin-like growth factor (IGF)
what is the complexity of neural induction?
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
late neurolation (after neural induction)
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
what is neural tube closer sensitive to?
nutrition and environmental toxins
-folic acid is particularly important, along with other B-complex vitamins, although the mechanism is unknown
spina bifida
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
anencephaly and holoprosencephaly
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
what happens to the neural crest after it pinches off?
(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
dorsal ventral patterning and how it makes such dorsal-ventral axis diversity
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
what does high sonic hedgehog expression do and where is it?
highly expressed only in the notochord and roof plate
-absence in the roof plate produces dorsal-ventral polarity
Shh signaling
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
developmental defects in Shh patterning and what this tells us about Shh regulation
- 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
cyclopamine
Shh antagonist that causes cyclopic sheep (in a plant they ate)
development of dorsal-ventral polarity in the spinal cord
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
anterior-posterior patterning and what they lead to
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)
A/P patterning below midbrain (posterior CNS) depends on what kind of genes?
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
where is there no Hox code?
proenscephalon and mesencephalon, so use EMX1, EMX2, OTX1, FGFs, and WNTs
what do OTX2 knockouts do?
show complete loss of anterior polarity
-knockout embryos completely lack forebrain neural structures
what regulates nervous system expansion?
coordination of symmetrical (divides into 2 of the same thing) and asymmetrical (2 different things) proliferation
what is required to organize distinct cell types
cell migration
ventricular zone
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
what is the choroid plexus?
makes the CSF
symmetric cell divisions
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
asymmetric cell divisions
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
how do precursor cells divide?
they can divide symmetrically and asymmetrically
which comes first: neurogenesis or gliogenesis?
neurogenesis precedes gliogenesis
molecular mechanisms regulating neural cell differentiation
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
how do Notch and proneural bHLH transcription factors control neural progenitor differentiation?
- 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 - 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
when does gliogenesis start?
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)
how long does neurogenesis last?
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
when the majority of gliogenesis happens?
after birth in humans
-almost no myelination in human at birth, and continues to increase to about 20 years old
when is primary neurulation complete?
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
general effects of alcohol and drugs on brain development
alcohol: smaller, not well folded
drugs: decrease in size of gray matter in cortex and caudate
neurogenesis and migration in cerebral cortex
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
radial migration regulated cortical layer formation
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
what regulates radial migration? what happens if there is a mutation?
Reelin; if there is a mutation, then there is “outside-in” layering such that first born cells can’t get past the older cells
how do interneurons migrate?
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
