Gremlin 2 regulates distinct roles of BMP and Endothelin 1 signaling in dorsoventral patterning of the facial skeleton

Zuniga, Elizabeth; Rippen, Marie; Alexander, Courtney; Schilling, Thomas F.; Crump, J. Gage

doi:10.1242/dev.067785

Cited by 79 publications

(180 citation statements)

References 49 publications

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“…4M,N; 60%, n5). Similar results were obtained in heat-shocked Tg(hsp70I:Gal4;UAS:Bmp4) embryos (Zuniga et al, 2011). Taken together with the loss-of-function data, these results suggest that hand2 is particularly sensitive to BMP signaling in the ventral arches, whereas expression of dlx6a and other intermediate-domain genes appears less sensitive.…”

Section: Bmps Are Sufficient To Induce Ventral Arch Identitiessupporting

confidence: 83%

“…6). Similarly, Tg(hsp70I:Gal4;UAS:Edn1) transgenics heat shocked between 16 and 28 hpf failed to rescue hand2 expression in BMP-deficient embryos (Zuniga et al, 2011). These results confirm the hand2 expression is BMP-dependent at both early and later stages of arch development.…”

Section: B) (Cd)isolated Cartilages Of the Mandibular (1) And Hyoisupporting

confidence: 60%

“…Later, the roles of BMPs and Edn1 become spatially distinct, with BMPs inducing the ventral-most fates within the arch while Edn1 induces more intermediate fates ( Fig. 8B; Zuniga et al, 2011). Our model helps reconcile the fact that BMPs and Edn1 are both required for ventral arch development.…”

Section: Discussionmentioning

confidence: 62%

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Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton

et al. 2011

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SUMMARYBone morphogenetic proteins (BMPs) play crucial roles in craniofacial development but little is known about their interactions with other signals, such as Endothelin 1 (Edn1) and Jagged/Notch, which pattern the dorsal-ventral (DV) axis of the pharyngeal arches. Here, we use transgenic zebrafish to monitor and perturb BMP signaling during arch formation. With a BMP-responsive transgene, Tg(Bre:GFP), we show active BMP signaling in neural crest (NC)-derived skeletal precursors of the ventral arches, and in surrounding epithelia. Loss-of-function studies using a heat shock-inducible, dominant-negative BMP receptor 1a [Tg(hs70I:dnBmpr1a-GFP)] to bypass early roles show that BMP signaling is required for ventral arch development just after NC migration, the same stages at which we detect Tg(Bre:GFP). Inhibition of BMP signaling at these stages reduces expression of the ventral signal Edn1, as well as ventral-specific genes such as hand2 and dlx6a in the arches, and expands expression of the dorsal signal jag1b. This results in a loss or reduction of ventral and intermediate skeletal elements and a mis-shapen dorsal arch skeleton. Conversely, ectopic BMP causes dorsal expansion of ventral-specific gene expression and corresponding reductions/transformations of dorsal cartilages. Soon after NC migration, BMP is required to induce Edn1 and overexpression of either signal partially rescues ventral skeletal defects in embryos deficient for the other. However, once arch primordia are established the effects of BMPs become restricted to more ventral and anterior (palate) domains, which do not depend on Edn1. This suggests that BMPs act upstream and in parallel to Edn1 to promote ventral fates in the arches during early DV patterning, but later acquire distinct roles that further subdivide the identities of NC cells to pattern the craniofacial skeleton.

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Section: Bmps Are Sufficient To Induce Ventral Arch Identitiessupporting

confidence: 83%

Section: B) (Cd)isolated Cartilages Of the Mandibular (1) And Hyoisupporting

confidence: 60%

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Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton

et al. 2011

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“…The Bmp pathway plays key roles in morphogenesis and development of the endoderm and CNCCs Davis et al, 2004;Miura et al, 2010;Paca et al, 2012;Poulain et al, 2006;Tiso et al, 2002;Yamamoto et al, 2009;Zuniga et al, 2011). Although we have gained a better understanding of the role of Bmp in CNCC development, how Bmp signaling regulates endoderm development remains poorly understood.…”

Section: Bmp Signaling Regulates Endoderm and Craniofacial Developmentmentioning

confidence: 99%

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish

et al. 2016

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The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face.

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“…In zebrafish, an interplay between Bmp and Edn signaling is important for branchial arch dorsoventral patterning Zuniga et al, 2011). Edn-deficient embryos display mandibular-to-maxillary transformations that are restricted to the Hox-negative CNC (Gitton The Dlx5/6 genes, targets for Edn signaling and direct regulators of Hand2, are also crucially important in facial development (Depew et al, 2002).…”

Section: Bmp Promotes Skeletal Differentiation From Cnc Progenitorsmentioning

confidence: 99%

Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development

et al. 2012

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SUMMARYWe performed an in depth analysis of Bmp4, a critical regulator of development, disease, and evolution, in cranial neural crest (CNC). Conditional Bmp4 overexpression, using a tetracycline-regulated Bmp4 gain-of-function allele, resulted in facial skeletal changes that were most dramatic after an E10.5 Bmp4 induction. Expression profiling uncovered a signature of Bmp4-induced genes (BIG) composed predominantly of transcriptional regulators that control self-renewal, osteoblast differentiation and negative Bmp autoregulation. The complimentary experiment, CNC inactivation of Bmp2, Bmp4 and Bmp7, resulted in complete or partial loss of multiple CNC-derived skeletal elements, revealing a crucial requirement for Bmp signaling in membranous bone and cartilage development. Importantly, the BIG signature was reduced in Bmp loss-of-function mutants, indicating Bmpregulated target genes are modulated by Bmp dose. Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG signature, including Satb2, Smad6, Hand1, Gadd45 and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation. These data support the hypothesis that Bmp signaling regulates craniofacial skeletal development by balancing self-renewal and differentiation pathways in CNC progenitors.

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Gremlin 2 regulates distinct roles of BMP and Endothelin 1 signaling in dorsoventral patterning of the facial skeleton

Cited by 79 publications

References 49 publications

Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton

Combinatorial roles for BMPs and Endothelin 1 in patterning the dorsal-ventral axis of the craniofacial skeleton

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish

Bmp signaling regulates a dose-dependent transcriptional program to control facial skeletal development

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