Induced haploinsufficiency of Kit receptor tyrosine kinase impairs brain development

Aoki, Hitomi; Hara, Akira; Kunisada, Takahiro

doi:10.1172/jci.insight.94385

Cited by 10 publications

(13 citation statements)

References 44 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This could be the result of compensatory gene expression [20,21] , or just an imagined Kit is only expressed, but not really functioning. A recent experiment that induced haploinsu ciency of Kit in the early phase of brain development caused serious hypoplasia of the central nervous system (Aoki et al [13] and Supplemental Fig. 1a), strongly indicating that Kit functions in the developing brain.…”

Section: Resultsmentioning

confidence: 88%

“…Therefore, we hypothesized that in well-characterized germline Kit mutants, some compensatory gene are expressed to substitute for Kit's vital function at early stages of brain development. In stage-speci c conditional knockout of Kit in the brain, the sudden decrease in Kit receptor expression and function in brain cells is supposed not to allow enough time for the assumed compensatory gene(s) to reactively increase its expression [13] . In other words, very little phenotypic disorder in the germline Kit mutant brain could be explained by a negative feedback system that enables seamless compensatory gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…For this purpose, we quanti ed gene expression in germline Kit mutant brains at various developmental stages. Since 60% of brain cells are expected to express Kit on their surface (Aoki et al [13] ; Supplemental Fig. 1b), possible gene expression changes expected to occur in those Kit expressing brain cells are likely to be detected by transcriptome analysis of whole brain mRNA samples.…”

Section: Resultsmentioning

confidence: 99%

“…In germ-line Kit loss-of-function mutants, the indispensable Kit function could be genetically compensated during embryogenesis, whereas conditional haploinsu ciency suddenly evoked in the neural precursor cells by the Sox1-Cre apparatus was not fully restored by the privileged compensatory system [13] . This raises the question of what gene(s) are compensatory in the germ line Kit mutant brain?…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Compensatory gene expression potentially rescues impaired brain development in Kit mutant mice

Minei

Aoki

Ogura

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

While loss-of-function mutations in the murine dominant white spotting/Kit (W) locus affect a diverse array of cell lineages, the brain and organs with the highest expression show the least number of defective phenotypes. We performed transcriptome analysis of the brains of KitW embryos and found prominent gene expression changes specifically in the E12.5 KitW/W homozygous mutant. Although other potentially causative changes in gene expression were observed, uniform downregulation of ribosomal protein genes and oxidative phosphorylation pathway genes specifically observed in the E12.5 brain may comprise a genetic compensation system exerting protective metabolic effects against the deleterious effect of KitW/W mutation in the developing brain.

show abstract

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Compensatory gene expression potentially rescues impaired brain development in Kit mutant mice

Minei

Aoki

Ogura

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The top-ranked SNPs detected in the PGC-OCD GWAS were in linkage disequilibrium with genes previously associated with autism spectrum disorders (ASD) 31 : GRID2 , involved in cerebellar synaptic processes 32 , and KIT , implicated in neurodevelopment 33 . Moreover, a sex-stratified GWAS of the PGC-OCD sample revealed that SNPs with sex-specific effects were significantly enriched for genome regions influencing gene expression (i.e.…”

Section: Genome Variantsmentioning

confidence: 95%

Cutting-edge genetics in obsessive-compulsive disorder

Saraiva¹,

Cappi²,

Simpson³

et al. 2020

Fac Rev

View full text Add to dashboard Cite

This article reviews recent advances in the genetics of obsessive-compulsive disorder (OCD). We cover work on the following: genome-wide association studies, whole-exome sequencing studies, copy number variation studies, gene expression, polygenic risk scores, gene–environment interaction, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. Findings from this work underscore the notion that the genetic architecture of OCD is highly complex and shared with other neuropsychiatric disorders. Also, the latest evidence points to the participation of gene networks involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems in this disorder. We conclude by highlighting that further study of the genetic architecture of OCD, a great part of which remains to be elucidated, could benefit the development of diagnostic and therapeutic approaches based on the biological basis of the disorder. Studies to date revealed that OCD is not a simple homogeneous entity, but rather that the underlying biological pathways are variable and heterogenous. We can expect that translation from bench to bedside, through continuous effort and collaborative work, will ultimately transform our understanding of what causes OCD and thus how best to treat it.

show abstract