Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Firulli, Beth A.; Fuchs, Robyn K.; Vincentz, Joshua W.; Clouthier, David E.; Firulli, Anthony B.

doi:10.1242/dev.107680

Cited by 28 publications

(45 citation statements)

References 67 publications

(78 reference statements)

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“…Rather, the observed defects likely arise during later differentiation of the NCC derived mesenchyme. Similar midfacial defects have recently been described in embryos containing phosphorylation variants of the bHLH factor Hand1 (Firulli et al, 2014). While the basis for the defects in these embryos is not completely clear, Hand1 is a downstream mediator of EDNRA signaling, suggesting the cellular affect of the two may share a common mechanism.…”

Section: Resultssupporting

confidence: 77%

Cre recombinase-regulated Endothelin1 transgenic mouse lines: Novel tools for analysis of embryonic and adult disorders

Tavares

Clouthier

2015

Developmental Biology

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Endothelin-1 (EDN1) influences both craniofacial and cardiovascular development and a number of adult physiological conditions by binding to one or both of the known endothelin receptors, thus initiating multiple signaling cascades. Animal models containing both conventional and conditional loss of the Edn1 gene have been used to dissect EDN1 function in both embryos and adults. However, while transgenic Edn1 over-expression or targeted genomic insertion of Edn1 has been performed to understand how elevated levels of Edn1 result in or exacerbate disease states, an animal model in which Edn1 over-expression can be achieved in a spatiotemporal-specific manner has not been reported. Here we describe the creation of Edn1 conditional over-expression transgenic mouse lines in which the chicken β-actin promoter and an Edn1 cDNA are separated by a strong stop sequence flanked by loxP sites. In the presence of Cre, the stop cassette is removed, leading to Edn1 expression. Using the Wnt1-Cre strain, in which Cre expression is targeted to the Wnt1-expressing domain of the central nervous system (CNS) from which neural crest cells (NCCs) arise, we show that stable CBA-Edn1 transgenic lines with varying EDN1 protein levels develop defects in NCC-derived tissues of the face, though the severity differs between lines. We also show that Edn1 expression can be achieved in other embryonic tissues utilizing other Cre strains, with this expression also resulting in developmental defects. CBA-Edn1 transgenic mice will be useful in investigating diverse aspects of EDN1-mediated-development and disease, including understanding how NCCs achieve and maintain a positional and functional identity and how aberrant EDN1 levels can lead to multiple physiological changes and diseases.

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Section: Resultssupporting

confidence: 77%

Cre recombinase-regulated Endothelin1 transgenic mouse lines: Novel tools for analysis of embryonic and adult disorders

Tavares

Clouthier

2015

Developmental Biology

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“…In addition, this module includes a secondary network involving cell-cell junctions (Jph2, Des, Popdc2, Mtus2) and outliers suggesting neural function (Syt6, Chrna6, Trpm1). Because five genes in this module are involved in proximal-distal patterning of the mandible (Hand1, Nkx3-2; Lettice et al, 1999; Firulli et al, 2014; reviewed in Clouthier et al, 2013) and/or are regulated by the distal mandible patterning genes Dlx5/6 (Dlx1as, Hand1, Cited1, Rgs5; Jeong et al, 2008), we interpret the core network as patterning the mandible proximal-distal axis. If co-expression indeed reflects shared function, then this module also predicts that mandible patterning involves a cell-cell junction sub-network, the orphan GPCR Gpr50, the signal transduction/hypospadias (urethral fusion) risk factor Dgkk (van der Zanden et al, 2011), and the endosome recycling factor Magel2 (Hao et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

Systems biology of facial development: contributions of ectoderm and mesenchyme

Hooper

Feng

et al. 2017

Developmental Biology

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The rapid increase in gene-centric biological knowledge coupled with analytic approaches for genomewide data integration provides an opportunity to develop systems-level understanding of facial development. Experimental analyses have demonstrated the importance of signaling between the surface ectoderm and the underlying mesenchyme in coordinating facial patterning. However, current transcriptome data from the developing vertebrate face is dominated by the mesenchymal component, and the contributions of the ectoderm are not easily identified. We have generated transcriptome datasets from critical periods of mouse face formation that enable gene expression to be analyzed with respect to time, prominence, and tissue layer. Notably, by separating the ectoderm and mesenchyme we considerably improved the sensitivity compared to data obtained from whole prominences, with more genes detected over a wider dynamic range. From these data we generated a detailed description of ectoderm-specific developmental programs, including pan-ectodermal programs, prominence- specific programs and their temporal dynamics. The genes and pathways represented in these programs provide mechanistic insights into several aspects of ectodermal development. We also used these data to identify co-expression modules specific to facial development. We then used 14 co-expression modules enriched for genes involved in orofacial clefts to make specific mechanistic predictions about genes involved in tongue specification, in nasal process patterning and in jaw development. Our multidimensional gene expression dataset is a unique resource for systems analysis of the developing face; our co-expression modules are a resource for predicting functions of poorly annotated genes, or for predicting roles for genes that have yet to be studied in the context of facial development; and our analytic approaches provide a paradigm for analysis of other complex developmental programs.

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“…It is likely that the disruption of BMP signaling and downstream BMP targets such as H1 and H2 feeds back upon Fgf8 hinge expression. Indeed, in H1 dimer mutants, Fgf8 levels are markedly increased (6).…”

Section: Discussionmentioning

confidence: 99%

“…H1 expression is confined to the distal cap ectomesenchyme (4,5). H1 dimer mutants display noncell-autonomous craniofacial phenotypes outside of the distal cap (6). The H1…”

Section: The H1mentioning

confidence: 99%

Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

Vincentz

Casasnovas

Barnes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cranial neural crest cells (crNCCs) migrate from the neural tube to the pharyngeal arches (PAs) of the developing embryo and, subsequently, differentiate into bone and connective tissue to form the mandible. Within the PAs, crNCCs respond to local signaling cues to partition into the proximo-distally oriented subdomains that convey positional information to these developing tissues. Here, we show that the distal-most of these subdomains, the distal cap, is marked by expression of the transcription factor Hand1 (H1) and gives rise to the ectomesenchymal derivatives of the lower incisors. We uncover a H1 enhancer sufficient to drive reporter gene expression within the crNCCs of the distal cap. We show that bone morphogenic protein (BMP) signaling and the transcription factor HAND2 (H2) synergistically regulate H1 distal cap expression. Furthermore, the homeodomain proteins distal-less homeobox 5 (DLX5) and DLX6 reciprocally inhibit BMP/H2-mediated H1 enhancer regulation. These findings provide insights into how multiple signaling pathways direct transcriptional outcomes that pattern the developing jaw.Bmp | DLX | HAND1 | cranial neural crest cells | development A fter migrating to specific locations within the developing embryo, neural crest cells (NCCs), a multipotent cell population originating from the dorsal lip of the neural tube, respond to local morphogenetic signaling cues to pattern and differentiate (1). Following migration to the pharyngeal arches (PAs), cranial NCCs (crNCCs) respond to endothelin 1 (EDN1) and bone morphogenic protein (BMP) signaling from surrounding pharyngeal epithelia to subdivide the PA ectomesenchyme into discrete proximo-distal domains (2). In the mandibular arch (MD1), these nested PA subdomains, characterized by the expression of DLX homeobox and/or HAND basic helix-loop-helix (bHLH) transcription factors, are integral to the development of specific jaw structures, including bone, tongue mesenchyme, and heterogeneous teeth (3). HAND factors regulate mandibular incisor development (4), whereas DLX proteins influence maxillary molar development (2). The mechanisms by which DLX-and HANDdependent transcriptional programs establish proximo-distal PA subdomains are poorly understood. Indeed, the dearth of identified cis-regulatory elements active in postmigratory NCCs has hampered the elucidation of the gene regulatory networks that establish regional identity within the developing mandible.BMP and EDN1 signaling initially overlaps within the distal murine MD1, but by embryonic day (E)10.5, these signaling pathways become spatially segregated. The distal-most tip of the PAs, known as the distal cap, is transiently devoid of active EDN1 signaling. BMP signaling is ostensibly restricted to this distal cap by the localized expression of Bmp antagonists (3). Here, we provide evidence that DLX5 and DLX6 act as transcriptional repressors of BMP signaling specifically within the cranial PAs. We show that, within the crNCCs, the BMP-dependent transcription factors Smads, H2, and GATA2/3 provi...

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Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

Cited by 28 publications

References 67 publications

Cre recombinase-regulated Endothelin1 transgenic mouse lines: Novel tools for analysis of embryonic and adult disorders

Cre recombinase-regulated Endothelin1 transgenic mouse lines: Novel tools for analysis of embryonic and adult disorders

Systems biology of facial development: contributions of ectoderm and mesenchyme

Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

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