Variants in nuclear factor I genes influence growth and development

Zenker, Martin; Bunt, Jens; Schanze, Ina; Schanze, Denny; Piper, Michael; Priolo, Manuela; Gerkes, Erica H.; Gronostajski, Richard M.; Richards, Linda J.; Vogt, Julie; Wessels, Marja W.; Hennekam, Raoul C. M.

doi:10.1002/ajmg.c.31747

Cited by 39 publications

(48 citation statements)

References 112 publications

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“…In V1, these markers include members of the Nuclear Factor I family, NFIA, NFIB and NFIX. These genes are important regulators of brain development and have been implicated in developmental disorders including macrocephaly and severe cognitive impairment 29 . They also include ZBTB18/RP58, a transcription factor involved in neuron differentiation and cortical migration and a putative driver of brain expansion 30,31 .…”

Section: Introduction and Resultsmentioning

confidence: 99%

An Atlas of Cortical Arealization Identifies Dynamic Molecular Signatures

Bhaduri

Sandoval-Espinosa

Otero-García³

et al. 2021

Preprint

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The human brain is subdivided into distinct anatomical structures. The neocortex, one of these structures, enables higher-order sensory, associative, and cognitive functions, and in turn encompasses dozens of distinct specialized cortical areas. Early morphogenetic gradients are known to establish an early blueprint for the specification of brain regions and cortical areas. Furthermore, recent studies have uncovered distinct transcriptomic signatures between opposing poles of the developing neocortex1. However, how early, broad developmental patterns result in finer and more discrete spatial differences across the adult human brain remains poorly understood2. Here, we use single-cell RNA-sequencing to profile ten major brain structures and six neocortical areas during peak neurogenesis and early gliogenesis. Our data reveal that distinct cell subtypes are predominantly brain-structure specific. Within the neocortex, we find that even early in the second trimester, a large number of genes are differentially expressed across distinct cortical areas in all cell types, including radial glia, the neural progenitors of the cortex. However, the abundance of areal transcriptomic signatures increases as radial glia differentiate into intermediate progenitor cells and ultimately give rise to excitatory neurons. Using an automated, multiplexed single-molecule fluorescent in situ hybridization (smFISH) approach, we validated the expression pattern of area-specific neuronal genes and also discover that laminar gene expression patterns are highly dynamic across cortical regions. Together, our data suggest that early cortical areal patterning is defined by strong, mutually exclusive frontal and occipital gene expression signatures, with resulting gradients giving rise to the specification of areas between these two poles throughout successive developmental timepoints.

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Section: Introduction and Resultsmentioning

confidence: 99%

An Atlas of Cortical Arealization Identifies Dynamic Molecular Signatures

Bhaduri

Sandoval-Espinosa

Otero-García³

et al. 2021

Preprint

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“…Macrocephaly and structural brain anomalies including anomalous corpora callosa are additional common features (Zenker et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…These genes have been associated with overlapping phenotypes including DD/ID that tends to be milder with NFIA and NFIB compared to NFIX —a finding supported by the patients reported herein, who both have moderate developmental delays. Macrocephaly and structural brain anomalies including anomalous corpora callosa are additional common features (Zenker et al, 2019). Haploinsufficiency for the Nuclear Factor I family genes has also been associated with physical overgrowth, including tall stature that is reportedly more common with pathogenic NFIA variants, although interestingly, our two patients had heights in the 88th centile ( Z score 1.17) and 95th centile ( Z score 1.66) respectively at their most recent physical examinations.…”

Section: Discussionmentioning

confidence: 99%

“…The NFI (nuclear factor I) gene family comprises NFIA , NFIB , NFIC , and NFIX that encode a family of transcription factors implicated in the development of multiple organ systems in humans, including the brain. Haploinsufficiency for NFIA , NFIB , and NFIX is associated with developmental delays (DD) and intellectual disability (ID), structural brain anomalies, and macrocephaly, in addition to gene‐specific clinical findings (Zenker et al, 2019). Deficiency for Nfib has been previously reported in mouse models to be important in forebrain formation and the development of the lungs and mammary glands (Murtagh, Martin, & Gronostajski, 2003; Steele‐Perkins et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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The expanding spectrum of NFIB‐associated phenotypes in a diverse patient population—A report of two new patients

Barrus

Rego

Yip

et al. 2020

American J of Med Genetics Pt A

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NFIB (Nuclear Factor I B) haploinsufficiency has recently been identified as a cause of intellectual disability and macrocephaly. Here we describe two patients with pathogenic variants in NFIB. The first is a 6-year-old Latino male with developmental delays, mild hypotonia, facial anomalies, and brain magnetic resonance imaging findings comprising mild thinning of the corpus callosum, with more marked thinning of the splenium and blunting of the rostrum and cavum septum pellucidum. Exome sequencing identified a previously described de novo variant in NFIB, c.265C>T, predicting p.Arg89Ter. The second is a 5-year-old Latino male with developmental delays, hypotonia, dysmorphic features, a preauricular tag and pit, a small ventricular septal defect, and brain magnetic resonance imaging findings including a dysmorphic corpus callosum and a small posterior fossa. A single nucleotide polymorphism microarray identified a 92 kb interstitial deletion at 9p23 including several exons of NFIB and no other known genes. Our two patients add to the knowledge of this rare condition through our addition of new brain MRI findings and dysmorphic features. Additionally, these are the first known Latino patients to be described with NFIB haploinsufficiency, expanding our understanding of the associated facial features in diverse populations. Further data are needed to determine genotype-phenotype relationships for NFIB.

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“…Importantly, from all the transcription factors with 3fold expression difference between zones 1 and 4/5, the NFI paralogues NFIA, B, and X are the only ones that retain strong, zoneinfluenced expression from the early INP to the mOSN stage ( Figure 5A-D). These three members of the nuclear factor I (NFI) family of transcription factors control a plethora of developmental and cell specification processes (Gronostajski, 2000;Zenker et al, 2019), and were previously implicated OSN differentiation (Baumeister et al, 1999;Behrens et al, 2000). NFIs are expressed at higher levels in zone 4/5 cells, from INP to mOSN, with NFIA and NFIB being expressed higher in INPs and iOSNs, and NFIX being upregulated in mOSNs ( Figure 5E, Supplemental Figure 5B).…”

Section: Graded Expression Of Nfi Paralogues Implicates Them In Zonalmentioning

confidence: 91%

Homeotic Regulation of Olfactory Receptor Choice via NFI-dependent Heterochromatic Silencing and Genomic Compartmentalization

Bashkirova

Monahan

Campbell³

et al. 2020

Preprint

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Expression of one out of >1000 olfactory receptor (OR) genes is stochastic but, yet, spatially organized in stereotypic anatomical zones of the olfactory epithelium. We discovered that transition to higher zones coincides with gradual increase of H3K9me3/H3K79me3 and expansion of long-range genomic interactions across OR genes with ascending zonal identities. Within a zone, however, heterochromatin levels, and genomic interaction frequencies progressively decline along increasing zonal OR identities. Consequently, in each differentiating neuron only ORs with the correct zonal identity combine chromatin state and genomic compartmentalization properties compatible with future gene choice; ORs with lower zonal identities have high H3K79me3/H3K9me3 enrichment and are silenced, while ORs with higher zonal identities are excluded from activating genomic interactions and, thus, cannot be chosen. This process is regulated by the gradient expression of NFIA, B, and X, triple deletion of which causes homeotic transformations on zonal OR expression, heterochromatin formation and genomic compartmentalization.

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Variants in nuclear factor I genes influence growth and development

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 39 publications

References 112 publications

An Atlas of Cortical Arealization Identifies Dynamic Molecular Signatures

An Atlas of Cortical Arealization Identifies Dynamic Molecular Signatures

The expanding spectrum of NFIB‐associated phenotypes in a diverse patient population—A report of two new patients

Homeotic Regulation of Olfactory Receptor Choice via NFI-dependent Heterochromatic Silencing and Genomic Compartmentalization

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