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

Abstract

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.

Whole-genome sequence of the Tibetan frog Nanorana parkeri and the comparative evolution of tetrapod genomes

“…The tongue of most frogs can be flipped out quickly to catch insects and other prey, and their tongue is morphologically specialized to accomplish this function. HAND2 plays important roles in tongue morphogenesis by regulating expression levels of other genes, including Dlx5 and Dlx6 (22). PRDM16 is also necessary for normal palatogenesis (23).…”

Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis

“…Previously, we reported that Hand2 affects cell proliferation (Hendershot et al, 2008;Holler et al, 2010;Barron et al, 2011). The significant decrease observed in both neuron and glial cell numbers in Hand2 mutant ENS suggested that loss of Hand2 function in the NEP cells might cause this anomaly.…”

“…We have previously shown that Hand2 functions in neurogenesis (Hendershot et al, 2008), development of the cardiac outflow tract (Holler et al, 2010) and aspects of craniofacial morphogenesis (Barron et al, 2011) by regulating cell proliferation. Here, we show a significant decrease in the number of dividing NEP cells when Hand2 was deleted although there was only a slight decrease in the total number of neurons.…”

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

“…Targeted disruption of Twist1 in NCCs leads to defects in upper and lower jaw development (Bildsoe et al, 2009). NCC-specific deletion of Hand2 results in disruption of lower jaw and tongue development (Barron et al, 2011). These factors appear highly conserved during vertebrate evolution (Barnes and Firulli, 2009) and probably play similar roles in human facial development.…”