A UNIQUE MUSCLE; DISSECTING THE ROLE OF SIGNALING PATHWAYS IN DEVELOPMENTAL ANOMALIES OF THE TONGUE

Abstract

<h3>Background</h3> The vertebrate tongue is a complex muscular organ involved in mastication, taste sensation, and articulation. The tongue is affected in many syndromes, diseases, and malignancies. It has recently been shown that a cascade of signaling interactions between different cell populations during embryogenesis orchestrates the development of the tongue. In humans, a number of congenital abnormalities affect the gross morphology of the tongue and can occur in isolation or as part of a developmental syndrome such as aglossia, microglossia, macroglossia, and bifid tongue. <h3>Objective</h3> We present an overview of the gross anatomy and embryology of mammalian tongue development, review the clinical presentation of tongue anomalies, and briefly look at their genetic etiology. We focused on one of the anomalies in mouse models and utilized multiple genetic approaches to investigate local temporospatial requirements for sonic hedgehog (Shh) signaling during tongue development. <h3>Results</h3> Mice lacking a <i>Shh cis</i> enhancer, <i>MFCS4</i>, with reduced Shh in dorsal tongue epithelium, have perturbed lingual septum tendon formation and disrupted intrinsic muscle patterning, with these defects reproduced following global <i>Shh</i> deletion from E10.5 mouse embryos. Shh responsiveness was diminished in local cranial neural crest cell (CNCC) populations in both mutants. Shh targets these cells through primary cilium. CNCC-specific deletion of orofaciodigital syndrome 1, which encodes a ciliary protein, led to loss of normal myotube arrangement and microglossia. <h3>Conclusions</h3> We demonstrate the cause of microglossia in syndromes affecting Shh signaling and show that Shh signaling is required in the cranial neural crest cells for lingual tendon differentiation and intrinsic muscle patterning.