Hedgehog signaling patterns the oral-aboral axis of the mandibular arch.

Jingyue Xu,Han Liu,Yu Lan,Steven Potter,David E Clouthier,Rulang Jiang,Mike Adam

doi:10.7554/elife.40315

Abstract

Development of vertebrate jaws involves patterning neural crest-derived mesenchyme cells into distinct subpopulations along the proximal-distal and oral-aboral axes. Although the molecular mechanisms patterning the proximal-distal axis have been well studied, little is known regarding the mechanisms patterning the oral-aboral axis. Using unbiased single-cell RNA-seq analysis followed by in situ analysis of gene expression profiles, we show that Shh and Bmp4 signaling pathways are activated in a complementary pattern along the oral-aboral axis in mouse embryonic mandibular arch. Tissue-specific inactivation of hedgehog signaling in neural crest-derived mandibular mesenchyme led to expansion of BMP signaling activity to throughout the oral-aboral axis of the distal mandibular arch and subsequently duplication of dentary bone in the oral side of the mandible at the expense of tongue formation. Further studies indicate that hedgehog signaling acts through the Foxf1/2 transcription factors to specify the oral fate and pattern the oral-aboral axis of the mandibular mesenchyme.

Highlights

Formation of the jaws conferred a huge evolutionary advantage to the early vertebrates such that more than 99% of living vertebrates today have biting jaws as a primary feeding apparatus (Brazeau and Friedman, 2015; Janvier, 1996; Miyashita, 2016)
Whereas all of the pharyngeal arches form by cranial neural crest cells that populate between the embryonic foregut endoderm and ventral surface ectoderm, and neural crest cells populating each of the other pharyngeal arches are specified by a combination of colinearly expressed Hox genes, the neural crest cells populating the first arch are Hox-negative and their fates are primarily regulated by signaling molecules expressed in the arch epithelium (Minoux and Rijli, 2010; Miyashita, 2016; Trainor and Krumlauf, 2001)
Since we detected expanded activation of pSmad1/5/9 and Bmp4 target gene expression in the mandibular arch mesenchyme in the E10.5 Smoc/c;Hand2-Cre mutant embryos and since increased BMP signaling has been correlated with increased neural crest apoptosis in mouse embryos lacking both Noggin and Chordin, two endogenous antagonists of BMPs (Anderson et al, 2006; Stottmann et al, 2001), we investigated whether reducing the Bmp4 gene dosage could rescue mandibular morphogenesis in the Smoc/c;Hand2-Cre embryos

Summary

Introduction

Formation of the jaws conferred a huge evolutionary advantage to the early vertebrates such that more than 99% of living vertebrates today have biting jaws as a primary feeding apparatus (Brazeau and Friedman, 2015; Janvier, 1996; Miyashita, 2016). Central in the formation and evolution of the vertebrate jaws is the embryonic first pharyngeal arch, the rostral-most pharyngeal arch recognized in the embryo (Cerny et al, 2004; Kuratani, 2004; Kuratani, 2012; Miyashita, 2016). As has been demonstrated by cell lineage studies in both axolotl and chick embryos, neural crest cells in the dorsal portion of the first pharyngeal arch contribute to trabecular bones of the neural cranium whereas neural crest cells in the ventral portion of the first arch, referred to as the mandibular arch, give rise to skeletal elements of both the upper and lower jaws (Cerny et al, 2004; Kuratani et al, 2013).

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