Development of NS (1) Flashcards
Describe the development of the neural tube and give corresponding weeks.
3rd week dorsal ectoderm gives rise to the neural plate (over notochord), neural grove forms in the midline of neural plate (somites on both sides), neural folds on either side of neural groove meet dorsally and fuse to form the neural tube; called Neurulation
What portion of the neural tube becomes the brain and the spinal chord?
rostral portion will become the brain, caudal portion will become the spinal chord
where do the neural crest cells migrate and what do they give rise to in the nervous system?
migrate ventrally and laterally; PNS- dorsal root ganglion, peripheral and cranial nerve ganglia, autonomic ganglia, enteric ganglia, schwann cells, satellite cells; Pia and arachnoid of forebrain; chromaffin cells of adrenal medulla, melanocytes, bone and muscle of head
What do the neuroepithelial cells in the neural tube give rise to?
neurons and glia which make up the CNS
What is anencephaly?
failure of brain to form if rostral tube does not close
What is spina bifida with myeloschisis?
neural tube does not close and vertebral arches do not fuse
What is spina bifida with meningomyelocele?
vertebral arches do not fuse, spinal cord in sac close to the surface
What is spina bifida with meningocele?
vertebral arches do not fuse, sac present but spinal cord is in the normal position
What is spina bifida occulta?
vertebral arches do not fuse, no sac present
The CNS is initially divided into 3 vesicles, What are they and what do they give rise to?
Forebrain (prosencephalon)- cavity becomes lateral and third ventricles divides into telencephalon and diencephalon, midbrain (mesencephalon)- cavity gives rise to cerebral aqueduct, hindbrain (rhombencephalon)- cavity becomes fourth ventricle divides into metencephalon and myelencephalon
What are the 5 vesicles that develop from the 3?
Telencephalon, Diencephalon, Mesencephalon, Metencephalon, Myelencephalon
How is the brain stem and spinal cord regionalized?
alar and basal plates separated by sulcus limitans; alar plate adjacent to the roof plate on the dorsal side of spinal cord, basal adjacent to the floor plate on the ventral side of spinal cord; basal medial and ventral to alar in brain stem
What does the alar plate give rise to at brain stem level?
primarily sensory structures, general and special in posterior one and visceral sensation in the anterior one
What does the basal plate give rise to brain stem level?
primarily motor; medial- motor control of somatic function, lateral- motor control of visceral function
What does the alar plate give rise to at spinal level?
sensory ascending projection neurons and interneurons
What does the basal plate give rise to at spinal level?
motor neurons and interneurons
What are neurogenic placodes? Examples?
thickenings of ectoderm which give rise to neurons in PNS; otic, olfactory, trigeminal and epibranchial
What does the olfactory placode give rise to?
olfactory epithelium; 2 types of neurons- olfactory receptor (CN I) and GnRH neurons which migrate along olfactory nerve axons into the brain
What does the otic placode give rise to?
all neurons of cochlear ganglion and most of the vestibular ganglion
What does the trigeminal placode give rise to?
some of the neurons of trigeminal ganglion
What does the epibranchial placode give rise to?
some neurons of CN ganglia VII, IX, and X (remainder from neural crest or a mix)
What is neuronal migration? What are the types?
how neurons move from their birth site to the final locations (orientation with respect to pia matter); radial perpendicular to pia or tangential parallel to pia; radial is most common from ventricle to pia
Where are CNS stem cells typically located?
adjacent to ventricles in brain and central canal in spinal cord
What is in the intermediate zone?
contains most neurons in the adult CNS; aka mantle zone
What is in the marginal zone?
outermost layer by pia, primarily contains processes from neurons in the intermediate zone which is just inferior or medial
What order do the neurons of the cerebral cortex migrate in?
the deeper residing neurons (closer to the ventricles) are born and migrate first, and the more superficial are last; all inside out; utilize radial migration
What type of migration to gabergic neurons undergo?
tangential into the olfactory bulb via rostral migratory system and to the cerebral cortex from the medial ganglionic eminence (inferior side of ventricle to superior side passing rostrally)
What is different about cerebellar development?
relatively immature at birth; granule cells migrate radially inward from pial to ventricle; postnatal development of this structure explains striking motor achievements in the first year of life
What is Hirschsprung’s disease?
symptoms include lack of peristalsis and constriction of colon, primary defect is due to lack of neural crest-derived PS enteric ganglia; mutation in proto-oncogene RET accounts for 50%
Excess retinoic acid causes what?
craniofacial malformations; mechanism may have been disruption of neural crest migration
What is Kallman’s syndrome?
neither olfactory nerve or GnRH neurons reach the brain; consequently anosmic and hypogonadal; gene mutated in one form identified as KAL-1 which encodes an adhesion molecule
What is Lissencephaly?
smooth brain, no gyri; one cause is a defect in gene for platelet activating factor acetyl-hydrolase
What are the symptoms in the symptom cluster CRASH? What is the cause?
Corpus collasum hypoplasia, developmental intellectual disability (Retardation), Adducted thumbs, Spastic paraplegia and Hydrocephalus; mutations of adhesion molecule L1
What is the proposed hypothesis for Autism?
failure of apoptosis in developing brain
How are primary somatosensory neurons differentiate?
begin as bipolar in the dorsal root ganglion and change into pseudounipolar, one process enters the spinal cord dorsally (now myelinated by oligo), the other extends towards the periphery (myelinated by schwann)
How do motor neurons of spinal cord develop?
differentiate in ventral horns, axons exit ventral roots and terminate on muscles
What does the telencephalon develop into?
2 cerebral hemespheres, each with its own lateral ventricle; includes cerebral cortex, hippocampal formation, olfactory bulb, basal ganglia, and basal forebrain
Describe the cerebral cortex development.
becomes convoluted during development to increase SA without increasing head size, at 5 months invitro it is relatively smooth, at birth has folded in to form gyri and sulcus of mature cortex
What does the diencephalon develop into?
contains pineal gland, epithalamus, thalamus, hypothalamus, posterior pituitary, and neural retina, single midline space of the 3rd ventricle
What does the mesencephalon develop into?
the midbrain containing the superior and inferior colliculi, tegmentum with red nucleus and substantia niagra, space in center becomes cerebral aqueduct
What develops from the metencephalon?
pons and cerebellum; part of 4th ventricle
What develops from the myelencephalon?
medulla; part fourth ventricle; early on similar to spinal cord development
What are rhombomeres?
8 of them in the developing rhombencephalon, repeating segments associated with cranial nerves, present during development but not adult
What are the 3 flexures formed during development and at what stage?
cephalic and cervical at 3 vesicle stage, pontine at 5 vesicle stage
What flexure is seen in the brain at birth?
mesencephalic, on ventral surface
What changes are made to the brain postnatally?
400g to 1400g, oligodendrocytes myelinate until age 20, activity fine tunes neuronal connections and a lack of stimulation during early years may have permanent effects on synapse formation and cognitive functioning
What is FAS? What effects does alcohol have on neural development?
heavy drinking, developmental intellectual disability and facial malformation, even moderate to light can cause learning deficits; alcohol esp. interferes with cell adhesion molecule L1
What effects does protein deficiency have on neural development?
inadequate in utero and first 2 years result in developmental intellectual disability, during pregnancy it reduces total number of neurons produced, during 1st 2 years it effects neuronal differentiation and axon pathfinding
What effects does iodine deficiency have on neural development?
endemic cretinism is common but preventable cause of intellectual disability; iodine necessary for normal thyroid functioning, thyroid hormone necessary for brain development; inadequate maternal intake effects fetal neural development
What effects does PKU have on neural development?
if untreated leads to developmental intellectual disability, caused by mutation in gene effecting phenylalanine hydroxylase function, leads to excess phenylalanine, which results in hypomeylination of the brain; may be secondary to effects on axon maturation; can be lessened by PKU screen and limiting phenylalanine
What effects does lead poisoning have on neural development?
exposure during pregnancy leads to reduction in intelligence and behavioral problems, recent evidence indicates levels of lead greater than 2.5 micrograms/dL may adversely effect cognition; linear relationship btwn exposure amount and IQ
What are the conserved molecular pathways of development?
cell proliferation, patterning of body plan, organogenesis, and wiring of the nervous system
What role does BMP signaling play in neural induction?
BMPs inhibit neural induction of embryonic ectoderm
What inhibits BMP signaling allowing for neural induction?
Noggin, secreted by the notochord
Where are the EMX 1 and 2 transcription factors seen?
in the rostral forebrain
Where are the OTX 1 and 2 transcription factors seen?
from rostral forebrain to caudal midbrain
What is the role of engrailed genes and WNT signaling in antero-posterior patterning of the midbrain?
isthmus (secondary organizing center at junct of mid and hindbrain); 2 signaling molecules WNT1 and FGF8 secreted by isthmus control the differentiation of midbrain stem cells through activation of En transcription factors; in Wnt1 or En1/En2 mutation, midbrain and Ant part of hind brain are deleted
What is the role of hox genes in antero-posterior patterning of the midbrain?
genes expressed along AP axis of developing embryo, domains of expression correspond to linear arrangement on chr, regulates motor neuron identity in hind brain; boudnaries tightly correlated with rhomberic segmentationsof hind brain;mutation alters neuron identity (ex. facial->trigem) hox expression in hind brain regulated by retinoic acid
How does the effect of Retinoic acid change along the AP axis of developing embryo?
effects begin in hindbrain and increase caudally; NC derived from prospective hindbrain, homeotic transformation of prospective hindbrain segments due to change in boundaries of Hox expression explains congenital abnormalities with retinoic acid embryopathy
What role does BMP play in dorso-ventral patterning?
BMPs in the surface ectoderm induce the roof plate which becomes the source of BMPS, stem cells in the neural tube on the dorsal aspect are affected by BMPs causing activation of transcription factors for sensory neurons
What role does shh play in dorso-ventral patterning?
in the notochord induce the florplate which becomes the source of shh, which activates combo of transcription factors for motor neurons on ventral aspect;
What role does chordin/nogin play in dorso-ventral patterning?
needed to suppress dorsalizing effects of BMPS in the ventral part of the neural tube
What role does FGF and RA play in dorso-ventral patterning?
required for interneuron and motor neuron differentiation
In dorso-ventral patterning, what is the concept of a morhagen in respect to shh?
shh influences differentiation of stem cells in a concentration-dependent manner, low levels of shh on stem cells-> V1 interneurons; high levels of shh on stme cells-> motor neurons
What is holoprosencephaly?
malformation of brain, failure of forebrain to divide into hemespheres or lobes and upper face along the midline, can mild or severe, effected by mutations in shh; prevention of NC migration
How do neural stem cells differentiate (general)?
continuously sampling environment, either self-renewal, quiescent or differentiate along a particular lineage in response to extrinsic cues
What is notch signaling?
notch ligands expressed on plasma membrane (membrane bound) as heterodimeric receptors, 4 categories neurogenesis primarily just notch 1, cells in which notch signaling is committed tend to remain uncommitted due to inhibition of proneural genes
What factors effect oligodendrocytes and astrocyte differentiation?
from O2A progenitor, regulated by PDGF and CNTF ; PDGF from neighboring type I astrocytes causes O2A proliferation, at birth O2A lose responsiveness to PDGF; if no CNTF they become oligodendrocytes; later in presence of CNTF elaborated by type I astrocytes under mesoderm influence O2A become astrocytes
What is the make-up of a growth cone?
specialized sensory motor structures at distal ends of axons; central core rich in mitochondira, microtubules and organelles; and slender actin rich, receptor-laden, and highly motile extensions->filopodia; between filopodia is the lamellopodia
What is the function of the growth cone?
smaple microenvironment for guidance cues with receptor-laden filopodia; filopodia extend or retract in response to cues
Where are the growth cones navigating? composition?
ECM; GAGs, collagens, elastin, fibronectin and laminin; laminin major component of basal lamina, largely responsible for growth promoting ability of ECM (heterotrimers alpha, beta and gamma) recognized by integrin receptors on growth cones (intracellular domain bound to a-actin and Talin), laminin-integrin cause cytoskeletal rearrangement->propel GC
What role do cell adhesion molecules play with growth cones? What kind are involved?
promote axon growth; cadherins (Ca dependent cell adhesion) and IgG like adhesion molecules that promote Ca independent cell adhesion
What are the different kinds of cadherins?
E, N, P and VE are the classical, named for where they were found (N is neuronal); non-classical such as protocadherins- highly diverse and widely expressed in brain; cadherins interact with their own kinds and are linked to cytoskeletons through catenins
What are the different IgGs and their bonding?
IgG segments connected by disulfide bonds; N-cam (20 diff forms), generated by alternate splicing, capable of homophillic or heterophillic interactions as well as unrelated ligands (netrins - DCC and Ephrins- Eph receptors), mediate strong cell adhesion needed for tissue histogenesis and integrity; loss if lethal;
What are the midline repellants? How do they function?
interactions between Robo receptor family and their slit ligands; slit genes expressed by midline cells; prevents ipsilateral from corssing and contralateral from crossing a second time;
How do contralateral axons corss the midline with slit mediated repulsive cues?
midline cells secrete Netrin, attracts axons expressing netrin receptors DCC or UNC-5H toward the midline; these axons have low Robo1/Robo2 expression, presumably under Robo3 influence (anti Robo), thus silencing Robo-Slit repulsion before midline crossing; after crossing axons down-regulate Robo 3 and up regulate Robo1/2 establishing Robo-slit repulsion
What are the midline attractants? How do they work?
interactions btwn DCC receptor and Netrins; Netrins resemble laminin subunit, extend influence from short to long range; defects in Netrin/DCC in mammals prevents axons reaching/crossing the midline
When is netrin repulsive?
ex. trochlear out dorsal and around to ventral; mediated by expression of DCC together with UNC-5 on the same axon; attraction or repulsion is dependent on change in intracellular cAMP, cGMP, and Ca concentrations in response to Netrin-DCC or Netrin-DCC+Unc5 interactions
How are semaphorins and neurophilin and plexin receptors involved in axonal pathfinding?
seamphorins can be secreted (neurophilin receptors) for long range or membrane bound (Plexin receptors) for short range, act through multimeric receptor complexes; interaction with receptor leads to collapse of growth cones; in some instances it is a chemoattractant (cGMP depenedent)
Defects in semaphorins leads to what?
axon projection abnormalities- defasciculations, overshooting, misrouting, and aberrant transmissions
How do ephrins and Eph receptors work in axon path finding?
Ephrin A( tethered to membrane) or ephrin B (transmembrane ligands; Ephirin A interacts with EphAR and B with EphBR; best studied in retinotectal projection where they cause repulsion
How do the Ephirin B’s act in retinotectal projection?
ephirin B2 expressed in optic chiasm and interacts with EphB1 on axons of ipsilateral projecting retinal ganglion cells, causing repulsion from crossing the midline
How do the Ephirin A’s act in retinotectal projection?
target RGC axons (SC)has gradient expression of Ephirin A, higher posterior and lower anterior, axons of RGC from temporal side of retina with high EphA when moving posterior interacts with Ephirin A and is repelled remaining confined to anterior SC; axons of RGCs on nasal side are able to move toward posterior SC because they lack the strong repulsion
