NFIB is a governor of epithelial–melanocyte stem cell behaviour in a shared niche

Chang, Chen‐Ming; Pasolli, H. Amalia; Γιαννοπούλου, Ευγενία; Guasch, Géraldine; Gronostajski, Richard M.; Elemento, Olivier; Fuchs, Elaine

doi:10.1038/nature11847

Cited by 155 publications

(156 citation statements)

References 41 publications

(64 reference statements)

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“…NFIB influences stem cell maintenance and differentiation in several tissues including in the SVZ as part of a cross-regulatory network together with Pax6/Brg1 (Chang et al, 2013;Ninkovic et al, 2013 (Chang et al, 2013). We believe this is the first demonstration of a non-canonical Drosha-mediated regulation of adult stem cell fate through a niche-independent intrinsic pathway.…”

Section: Discussionmentioning

confidence: 83%

“…NFI transcription factors can activate and repress gene transcription depending on the gene and cellular context (Chang et al, 2013;Gronostajski, 2000;Messina et al, 2010). NFIB influences stem cell maintenance and differentiation in several tissues including in the SVZ as part of a cross-regulatory network together with Pax6/Brg1 (Chang et al, 2013;Ninkovic et al, 2013 (Chang et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

et al. 2016

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SUMMARYMulti-lineage neuronal, astrocytic and oligodendrocytic potential is considered a neural stem cell (NSC) trait. However, hippocampal NSCs generate neurons and astrocytes but not oligodendrocytes in vivo and how this is regulated is unknown. Here we show that the RNAseIII Drosha is an intrinsic regulator of stem cell maintenance and differentiation in the adult mouse hippocampus. Inactivation of Drosha results in exhaustion of the NSC pool, premature arrest of neurogenesis, and induction of oligodendrocyte fate commitment. Drosha silences Nuclear Factor IB (NFIB) in hippocampal NSCs by targeting a double-stranded hairpin in the NFIB mRNA, thereby repressing its expression in a Dicer and miRNA-independent manner. We show that NFIB is required and sufficient for oligodendrocyte fate and knockdown of NFIB rescues neurogenesis by Drosha-deficient hippocampal NSCs. Our findings reveal a novel mechanism for stem cell maintenance and oligodendrocyte fate restriction in the adult hippocampus.3

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

et al. 2016

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“…The medial mRNA sequencing was performed on neocortical tissue dissected from E16 Nfia and Nfib knockout mice. The 91 shared mis-regulated genes in Nfia and Nfib knockout mice were enriched for the presence of an NFI binding motif in their promoter, as compared to all genes in the genome, as well as all differentially regulated genes in either Nfia or Nfib knockout mice (a) Furthermore, the promoter regions of shared mis-regulated genes also displayed an enrichment for putative NFI binding sites, based on an increase in NFIB binding peaks in their promoter observed in ChIP-sequence data from mouse hair follicle stem cells (Chang et al, 2013) and E16 lung tissue (Lajoie et al, 2014) (b and c). This enrichment of putative NFI binding sites was predominantly observed in shared down-regulated genes observed between Nfia and Nfib knockout mice (striped pattern).…”

Section: Complete Allelic Loss Of Nfia and Nfib Results In A More Sevmentioning

confidence: 99%

“…To assess whether NFIB could bind to the promoter of these differentially expressed genes, we analysed the presence of an NFIB binding peak in their promoter using published NFIB chromatin immunoprecipitation-sequencing (ChIP-sequencing) data reported in other tissues (Chang et al, 2013;Lajoie et al, 2014). The presence of an NFIB binding peak detected within a gene promoter from a ChIP-sequencing dataset from mouse hair follicle stem cells increased from 1.1% in the promoter of all genes to 1.5% and 2.7% in the differentially regulated genes that we identified in the Nfia and Nfib knockout mice, respectively (Figure 4(b)).…”

Section: Shared Misregulated Genes In Nfi Knockout Neocortex Are Enrimentioning

confidence: 99%

“…To predict the presence of NFI binding motifs, we used the Find Individual Motif Occurrences tool (FIMO; Grant et al, 2011) with default programme significance threshold and the NFI motifs defined by Jolma et al (2013). Enrichment of NFIB binding peaks (Chang et al, 2013;Lajoie et al, 2014) in the promoter were analysed as described previously (Bunt et al, 2012) and significance was determined by a chi-square test with Yates' corrections.…”

Section: Rna Sequencing and Analysismentioning

confidence: 99%

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Combined allelic dosage of Nfia and Nfib regulates cortical development

Bunt

Osinski

Lim

et al. 2017

Brain and Neuroscience Advances

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Background: Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate similar biological processes, as their expression patterns, regulation of target genes and individual knockout phenotypes overlap. We hypothesised that the combined allelic loss of Nfia and Nfib would culminate in more severe defects in the cerebral cortex than loss of a single member. Methods: We combined immunofluorescence, co-immunoprecipitation, gene expression analysis and immunohistochemistry on knockout mouse models to investigate whether nuclear factor I A and nuclear factor I B function similarly and whether increasing allelic loss of Nfia and Nfib caused a more severe phenotype. Results: We determined that the biological functions of nuclear factor I A and nuclear factor I B overlap during early cortical development. These proteins are co-expressed and can form heterodimers in vivo. Differentially regulated genes that are shared between Nfia and Nfib knockout mice are highly enriched for nuclear factor I binding sites in their promoters and are associated with neurodevelopment. We found that compound heterozygous deletion of both genes resulted in a cortical phenotype similar to that of single homozygous Nfia or Nfib knockout embryos. This was characterised by retention of the interhemispheric fissure, dysgenesis of the corpus callosum and a malformed dentate gyrus. Double homozygous knockout of Nfia and Nfib resulted in a more severe phenotype, with increased ventricular enlargement and decreased numbers of differentiated glia and neurons. Conclusion: In the developing cerebral cortex, nuclear factor I A and nuclear factor I B share similar biological functions and function additively, as the combined allelic loss of these genes directly correlates with the severity of the developmental brain phenotype.

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Recurrent NFIA K125E substitution represents a loss‐of‐function allele: Sensitive in vitro and in vivo assays for nontruncating alleles

Uehara

Sanuki

Ogura

et al. 2021

American J of Med Genetics Pt A

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Nuclear factor I A (NFIA) is a transcription factor that belongs to the NFI family. Truncating variants or intragenic deletion of the NFIA gene are known to cause the human neurodevelopmental disorder known as NFIA‐related disorder, but no patient heterozygous for a missense mutation has been reported. Here, we document two unrelated patients with typical phenotypic features of the NFIA‐related disorder who shared a missense variant p.Lys125Glu (K125E) in the NFIA gene. Patient 1 was a 6‐year‐old female with global developmental delay, corpus callosum anomaly, macrocephaly, and dysmorphic facial features. Patient 2 was a 14‐month‐old male with corpus callosum anomaly and macrocephaly. By using Drosophila and zebrafish models, we functionally evaluated the effect of the K125E substitution. Ectopic expression of wild‐type human NFIA in Drosophila caused developmental defects such as eye malformation and premature death, while that of human NFIA K125E variant allele did not. nfia‐deficient zebrafish embryos showed defects of midline‐crossing axons in the midbrain/hindbrain boundary. This impairment of commissural neurons was rescued by expression of wild‐type human NFIA, but not by that of mutant variant harboring K125E substitution. In accordance with these in vivo functional analyses, we showed that the K125E mutation impaired the transcriptional regulation of HES1 promoter in cultured cells. Taken together, we concluded that the K125E variant in the NFIA gene is a loss‐of‐function mutation.

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NFIB is a governor of epithelial–melanocyte stem cell behaviour in a shared niche

Cited by 155 publications

References 41 publications

Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

Multipotency of Adult Hippocampal NSCs In Vivo Is Restricted by Drosha/NFIB

Combined allelic dosage of Nfia and Nfib regulates cortical development

Recurrent NFIA K125E substitution represents a loss‐of‐function allele: Sensitive in vitro and in vivo assays for nontruncating alleles

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