Cerebellar Development Flashcards
cerebellum
originates in the hindbrain (shown in lamprey studies)
folded into folia - rectilinear (has many perpendicular structures)
organisms vary in the number of cerebellar cells
functions of the cerebellum
motor coordination
fine control of movement & motor learning
comparator
proprioception
errors in the function of the cerebellum
posture
ataxia (abnormally coordinated muscle contractions)
intention tremor (movement activation delay e.g. parkinsonism tremor)
type of coordination used by the cerebellum
ipsilateral coordination (right cerebellum to right arm)
rhythmic sensorimotor synchronisation
feedforward control system in goldfish
anticipates an error which causes a function e.g. memory
cognitive disorders
cerebellar affective disorder - affects emotion/language/sensors
ASD - smaller/larger cerebellum
emotion & executive decision
cell types in the cerebellum
Purkinje cells
granule cells
inhibitory neurons (molecular layer interneurons/golgi cells)
deep cerebellar nuclei (fire APs)
cortical/outer layer architecture
molecular layer (many axons and dendrites)
Purkinje cells (output to deep nuclei)
granule cell (input from all areas)
2 forms of excitatory inputs
climbing fibres
mossy fibres
where are inhibitory projections sent to
inferior olive
what maps the regional boundaries of the cerebellum
isthmus (organiser) divides the mesencephalon from the hindbrain, separates MB from the HB, contributes to feathers, secretes FGF
Mapping the isthmus
with a surgical chimaera
Hallonet et al, 1990
swap brain regions between quail and chick embryo: Entire hindbrain (metencephalic vesicle) exchange, Half hindbrain exchange, Midbrain (diencephalic and mesencephalic vesicles) exchange
results: longitudinal movements stretch and distort the early neural tube, purkinje cells orginate from the same region as the ventricular epithelium
gene expression for isthmus positioning
increased Otx2 (MB) - deletion loses entire head
Gbx2 - positions isthmus
decreased Hoxa2
gap between otx2 and hoxa2 is where cerebellum appears (r1)
r1 - where all purkinje cells and granule cells form
what is the cerebellum derived from
Dorsal: dl1 Math1 (atoh1)
ventral: dl4/5 Ptf1a
bHLH (TF) genes in different DV domains
mapping granule cell origins with Math1 genetic fate map
Machold & Fishell , 2005
cross MATH1CreERT2 and R26R mice
tamoxifen activates lacZ and binds to ERT2 (estrogen R), cre activated, cre removes floxed stop sequence from lacZ, lacZ turned on, permanent B-gal expression
MATH1 controls cre
granule cells travel on surface then migrate inwards
where are granule cells born
rhombic lip
migrate to the external germinal layer (EGL)
math1 (mouse atonal)
expressed at the rhombic lip and EGL
causes cell migration and is needed for granule cells
methods to understand cerebellar development
single cell RNA sequencing
whole CNS projection training
STARmap spatial transcriptomics
DV patterning
BMP/Wnt released in the roofplate
Shh released in the floorplate
cerebellar development landmarks
shh secreted by purkinje cells/proliferative EGL
transient superficial granule layer
tangenital granule migration
purkinje cells are where expansion occurs
what is transit amplification
stem cells are committed to one fate
cerebellar amplification occurs on the EGL (vs cortical amplification occurs in the SVZ)
steps in granule cell development (amniotes)
1) induction (TGFB at roofplate)
2) transit amplification (pc releases Shh)
3) radial migration
Atoh1 expressed in granule cell precursors
more Shh = bigger cerebellum
4 subgroups of medulloblastomas
MBshh (PTCH/SUFU/SMO/Gli2 amplification)
MBwnt (HB) (CTNNB1)
MBgrp3/4 (not related to Shh)
medulloblastoma
common childhood brain tumour
causal factor by: Shh disruption (Shh induces proliferation) , Shh-2 overactivity associated with mutations in PTCH1 receptor
is MB only caused by granule cell overproliferation
no
more recruitment of other cells: astrocytes/blood vessels/dormant tumours
what is the source of Grp3/4 tumours
human rhombic lip (produces Math1)
present for 36 weeks (long) , persists into advanced cerebellum, own transit amplifying layer (SV layer)
