Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Compound
Target Concepts:
Gene/Protein
Disease
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Query: UMLS:C0851184 (
thinning
)
11,252
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
WDR62
mutations that result in protein loss, truncation or single amino-acid substitutions are causative for human microcephaly, indicating critical roles in cell expansion required for brain development.
WDR62
missense mutations that retain protein expression represent partial loss-of-function mutants that may therefore provide specific insights into radial glial cell processes critical for brain growth. Here we utilized CRISPR/Cas9 approaches to generate three strains of
WDR62
mutant mice;
WDR62
V66M/V66M and WDR62R439H/R439H mice recapitulate conserved missense mutations found in humans with microcephaly, with the third strain being a null allele (WDR62stop/stop). Each of these mutations resulted in embryonic lethality to varying degrees and gross morphological defects consistent with ciliopathies (dwarfism, anophthalmia and microcephaly). We find that
WDR62
mutant proteins (V66M and R439H) localize to the basal body but fail to recruit CPAP. As a consequence, we observe deficient recruitment of IFT88, a protein that is required for cilia formation. This underpins the maintenance of radial glia as
WDR62
mutations caused premature differentiation of radial glia resulting in reduced generation of neurons and cortical
thinning
. These findings highlight the important role of the primary cilium in neocortical expansion and implicate ciliary dysfunction as underlying the pathology of MCPH2 patients.
...
PMID:The association of microcephaly protein WDR62 with CPAP/IFT88 is required for cilia formation and neocortical development. 3181 41
Primary microcephaly genes (
MCPH
) are required for the embryonic expansion of the mammalian cerebral cortex. However,
MCPH
mutations may spare growth in other regions of the developing forebrain which reinforces context-dependent functions for distinct
MCPH
genes in neurodevelopment. Mutations in the
MCPH2
gene,
WD40-repeat protein 62
(
WDR62
), are causative of primary microcephaly and cortical malformations in humans.
WDR62
is a spindle microtubule-associated phosphoprotein that is required for timely and oriented cell divisions. Recent studies in rodent models confirm that
WDR62
loss or mutation causes
thinning
of the neocortex and disrupted proliferation of apical progenitors reinforcing critical requirements in the maintenance of radial glia. However, potential contributions for
WDR62
in hippocampal development had not been previously defined. Using CRISPR/Cas9 gene editing, we generated mouse models with patient-derived non-synonymous missense mutations (
WDR62
V66M
and
WDR62
R439H
) and a null mutation (herein referred to as
WDR62
Stop
) for comparison. We find that
WDR62
deletion or mutation resulted in a significant reduction in the thickness of the hippocampal ventricular zone and the area of the dentate gyrus (DG). This was associated with the mitotic arrest and depletion of radial glia and intermediate progenitors in the ammonic neuroepithelium. As a consequence, we find that the number of mitotic dentate precursors in the migratory stream and granule neurons in the DG was reduced with
WDR62
mutation. These findings reveal that
WDR62
is required for neurogenesis and the growth of the hippocampus during embryonic development.
...
PMID:The Spindle-Associated Microcephaly Protein, WDR62, Is Required for Neurogenesis and Development of the Hippocampus. 3304 90
