Regulation of facial morphogenesis by endothelin signaling: Insights from mice and fish

Clouthier, David E.; Garcia, Elvin L.; Schilling, Thomas F.

doi:10.1002/ajmg.a.33568

Cited by 91 publications

(109 citation statements)

References 95 publications

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“…Hand1 phospho-mutants show alterations in signaling pathways that regulate craniofacial formation During craniofacial formation, numerous signaling pathways intersect to govern normal morphological patterning and include Fgf, Shh, Wnt, Bmp and RA signaling (Clouthier et al, 2010;Trainor, 2005). We first looked at altered RA signaling as Rdh10 mutant mice exhibit similar mid-facial clefting (Sandell et al, 2007).…”

Section: Hand1 Phospho-mutant Expression Within the Pas Results In Prmentioning

confidence: 99%

“…Neural crest cells (NCCs) are a multipotent cell population that specifies within the dorsal lip of the neural tube and subsequently delaminates, migrates and populates the pharyngeal arches (PAs), before ultimately differentiating into a wide spectrum of structures/ tissues along the anterior-posterior (AP) axis of vertebrate embryos (Clouthier et al, 2010;Minoux and Rijli, 2010;Ruest and Clouthier, 2009;Trainor, 2005;Gitton et al, 2010). The NCCs that migrate into the first and second PAs are primarily responsible for orchestrating craniofacial development.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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In this study we examine the consequences of altering Hand1 phosphoregulation in the developing neural crest cells (NCCs) of mice. Whereas Hand1 deletion in NCCs reveals a nonessential role for Hand1 in craniofacial development and embryonic survival, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, in NCCs results in severe mid-facial clefting and neonatal death. Hand1 phosphorylation mutants exhibit a noncell-autonomous increase in pharyngeal arch cell death accompanied by alterations in Fgf8 and Shh pathway expression. Together, our data indicate that the extreme distal pharyngeal arch expression domain of Hand1 defines a novel bHLH-dependent activity, and that disruption of established Hand1 dimer phosphoregulation within this domain disrupts normal craniofacial patterning.

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Section: Hand1 Phospho-mutant Expression Within the Pas Results In Prmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Loss of Ednra, Edn1, or Dlx5 and Dlx6 results in homeotic transformation of mandibular arch-derived bone and soft tissue structures into more maxillarylike derivates (Beverdam et al, 2002;Depew et al, 2002;Ozeki et al, 2004;Ruest et al, 2004). However, aglossia is not observed in any mouse mutants in the Ednra pathway (Ednra,Edn1,Ece1,Mef2c,Dlx5,Dlx6) (Clouthier et al, 2010).…”

Section: Introductionmentioning

confidence: 92%

“…Ednra signaling is induced soon after NCCs reach the pharyngeal arches by its ligand, endothelin-1 (Edn1) Maemura et al, 1996;Miller et al, 2000;Yanagisawa et al, 1998). This initiates one or more signaling cascades responsible for NCC identity and fate within the mandibular pharyngeal arch (Clouthier et al, 2010;Clouthier and Schilling, 2004). Two induced factors, Dlx5 and Dlx6, contribute to the 'Dlx code' hypothesized to establish proximal-distal identity within the arches (Depew et al, 2002;Depew and Simpson, 2006;Depew et al, 2005;Jeong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis

et al. 2011

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SUMMARYLower jaw development is a complex process in which multiple signaling cascades establish a proximal-distal organization. These cascades are regulated both spatially and temporally and are constantly refined through both induction of normal signals and inhibition of inappropriate signals. The connective tissue of the tongue arises from cranial neural crest cell-derived ectomesenchyme within the mandibular portion of the first pharyngeal arch and is likely to be impacted by this signaling. Although the developmental mechanisms behind later aspects of tongue development, including innervation and taste acquisition, have been elucidated, the early patterning signals driving ectomesenchyme into a tongue lineage are largely unknown. We show here that the basic helix-loop-helix transcription factor Hand2 plays key roles in establishing the proximaldistal patterning of the mouse lower jaw, in part through establishing a negative-feedback loop in which Hand2 represses Dlx5 and Dlx6 expression in the distal arch ectomesenchyme following Dlx5-and Dlx6-mediated induction of Hand2 expression in the same region. Failure to repress distal Dlx5 and Dlx6 expression results in upregulation of Runx2 expression in the mandibular arch and the subsequent formation of aberrant bone in the lower jaw along with proximal-distal duplications. In addition, there is an absence of lateral lingual swelling expansion, from which the tongue arises, resulting in aglossia. Hand2 thus appears to establish a distal mandibular arch domain that is conducive for lower jaw development, including the initiation of tongue mesenchyme morphogenesis.

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“…Although cranial NC cells acquire their anterior-posterior identities (mandibular versus hyoid arch) prior to migration, patterning events at post-migratory stages largely determine the morphogenesis of individual skeletal elements (Trainor and Krumlauf, 2000;Schilling et al, 2001;Knight and Schilling, 2006). Overlapping expression domains of transcription factors of the Dlx family, as well as Hand2 (Clouthier et al, 2010) pattern each pharyngeal segment along its dorsal-ventral (D-V) axis (equivalent to the proximal-distal axis in mice). These early domains are induced by signals from surrounding epithelia, including the endoderm and ectoderm that line each arch (David et al, 2002;Trainor and Krumlauf, 2000); in the mandibular arch, for example, they roughly determine ventral (e.g.…”

Section: Introductionmentioning

confidence: 99%

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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Regulation of facial morphogenesis by endothelin signaling: Insights from mice and fish

Cited by 91 publications

References 95 publications

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

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

Downregulation of Dlx5 and Dlx6 expression by Hand2 is essential for initiation of tongue morphogenesis

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

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