BCL11B expression in intramembranous osteogenesis during murine craniofacial suture development

Holmes, Greg; Bakel, Harm van; Zhou, Xiaoli; Losic, Bojan; Jabs, Ethylin Wang

doi:10.1016/j.gep.2014.12.001

Cited by 13 publications

(13 citation statements)

References 44 publications

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“…High levels of BCL11B expression persisted at E14.5 and E16.5 within the facial skeleton, osteogenic fronts of frontal and parietal bones, in the coronal suture, and dura mater (Fig. 3A–F), consistent with previous report (Holmes et al, 2015). BCL11B expression appeared somewhat down-regulated within the facial and cranial skeleton by E18.5 (Fig.…”

Section: Resultssupporting

confidence: 91%

BCL11B regulates sutural patency in the mouse craniofacial skeleton

Kyrylkova¹,

Iwaniec²,

Philbrick³

et al. 2016

Developmental Biology

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The transcription factor BCL11B plays essential roles during development of the immune, nervous, and cutaneous systems. Here we show that BCL11B is expressed in both osteogenic and sutural mesenchyme of the developing craniofacial complex. Bcl11b−/− mice exhibit increased proliferation of osteoprogenitors, premature osteoblast differentiation, and enhanced skull mineralization leading to synostoses of facial and calvarial sutures. Ectopic expression of Fgfr2c, a gene implicated in craniosynostosis in mice and humans, and that of Runx2 was detected within the affected sutures of Bcl11b−/− mice. These data suggest that ectopic expression of Fgfr2c in the sutural mesenchyme, without concomitant changes in the expression of FGF ligands, appears to induce the RUNX2-dependent osteogenic program and craniosynostosis in Bcl11b−/− mice.

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Section: Resultssupporting

confidence: 91%

BCL11B regulates sutural patency in the mouse craniofacial skeleton

Kyrylkova¹,

Iwaniec²,

Philbrick³

et al. 2016

Developmental Biology

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“…2F). 25 The interorbital distance was substantially increased in bcl11ba morphant zebrafish, as in the patient (Fig. 2G and 2H).…”

Section: Resultsmentioning

confidence: 55%

Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

Punwani¹,

Zhang

Yu³

et al. 2016

N Engl J Med

105

106

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BACKGROUND Severe combined immunodeficiency (SCID) is characterized by arrested T-lymphocyte production and by B-lymphocyte dysfunction, which result in life-threatening infections. Early diagnosis of SCID through population-based screening of newborns can aid clinical management and help improve outcomes; it also permits the identification of previously unknown factors that are essential for lymphocyte development in humans. METHODS SCID was detected in a newborn before the onset of infections by means of screening of T-cell–receptor excision circles, a biomarker for thymic output. On confirmation of the condition, the affected infant was treated with allogeneic hematopoietic stem-cell transplantation. Exome sequencing in the patient and parents was followed by functional analysis of a prioritized candidate gene with the use of human hematopoietic stem cells and zebrafish embryos. RESULTS The infant had “leaky” SCID (i.e., a form of SCID in which a minimal degree of immune function is preserved), as well as craniofacial and dermal abnormalities and the absence of a corpus callosum; his immune deficit was fully corrected by hematopoietic stem-cell transplantation. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The resulting BCL11B protein had dominant negative activity, which abrogated the ability of wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration; this revealed a previously unknown function of BCL11B. The patient’s abnormalities, when recapitulated in bcl11ba-deficient zebrafish, were reversed by ectopic expression of functionally intact human BCL11B but not mutant human BCL11B. CONCLUSIONS Newborn screening facilitated the identification and treatment of a previously unknown cause of human SCID. Coupling exome sequencing with an evaluation of candidate genes in human hematopoietic stem cells and in zebrafish revealed that a constitutional BCL11B mutation caused human multisystem anomalies with SCID and also revealed a prethymic role for BCL11B in hematopoietic progenitors. (Funded by the National Institutes of Health and others.)

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“…Furthermore, the c.7C>A variant was not present in any database, including the Exome Aggregation Consortium (ExAC) and the Genome Aggregation Database (gnomAD) covering more than 120 000 exomes or genomes from unrelated individuals. The BCL11B variant was thought to likely be causally significant, as Bcl11b is expressed in cranial sutures (29,32), and Bcl11b −/− mice exhibit craniofacial abnormalities, including craniosynostosis (29). Furthermore, the p.R3S substitution occurs within a conserved amino-terminal domain found within a class of NuRD complex interacting transcription factors (Fig.…”

Section: Resultsmentioning

confidence: 99%

A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

Goos

Vogel

Mlčochová

et al. 2019

Human Molecular Genetics

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Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4–MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4–MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency.

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BCL11B expression in intramembranous osteogenesis during murine craniofacial suture development

Cited by 13 publications

References 44 publications

BCL11B regulates sutural patency in the mouse craniofacial skeleton

BCL11B regulates sutural patency in the mouse craniofacial skeleton

Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B

A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

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