The Dlx5 Homeobox Gene Is Essential for Vestibular Morphogenesis in the Mouse Embryo through a BMP4-Mediated Pathway

Abstract

In the mouse embryo, Dlx5 is expressed in the otic placode and vesicle, and later in the semicircular canals of the inner ear. In mice homozygous for a null Dlx5/LacZ allele, a severe dysmorphogenesis of the vestibular region is observed, characterized by the absence of semicircular canals and the shortening of the endolymphatic duct. Minor defects are observed in the cochlea, although Dlx5 is not expressed in this region. Cristae formation is severely impaired; however, sensory epithelial cells, recognized by calretinin immunostaining, are present in the vestibular epithelium of Dlx5(-/-) mice. The maculae of utricle and saccule are present but cells appear sparse and misplaced. The abnormal morphogenesis of the semicircular canals is accompanied by an altered distribution of proliferating and apoptotic cells. In the Dlx5(-/-) embryos, no changes in expression of Nkx5.1(Hmx3), Pax2, and Lfng have been seen, while expression of bone morphogenetic protein-4 (Bmp4) was drastically reduced. Notably, BMP4 has been shown to play a fundamental role in vestibular morphogenesis of the chick embryo. We propose that development of the semicircular canals and the vestibular inner ear requires the independent control of several homeobox genes, which appear to exert their function via tight regulation of BPM4 expression and the regional organization of cell differentiation, proliferation, and apoptosis.

Cranial expression of class 3 secreted semaphorins and their neuropilin receptors

“…The expression domain of Sema3D (Fig. 2V) closely mirrors that of Nkx5.1 (Merlo et al, 2002). This finding raises the possibility that NPN1 and Sema3D are downstream targets of these transcription factors.…”

“…The dorsolateral otic vesicle gives rise to the vestibular organ, whereas the ventromedial half forms the cochlear. Many genes that determine this differentiation are already localised to specific areas of the otic vesicle before any obvious morphologic changes are apparent (Torres and Giraldez, 1998;Merlo et al, 2002). We find that NPN1 and several of the semaphorins are also clearly restricted to certain regions of this pseudostratified epithelium.…”

“…2Q) correlates with that expressing Dlx5 (Merlo et al, 2002). Mice lacking this transcription factor have dysmorphogenesis of the vestibular organ (Merlo et al, 2002). The expression domain of Sema3D (Fig.…”

Molecular Genetics of Vestibular Organ Development

“…So far, only a knockout of Dlx5 has been reported to result in malformations of the inner ear, including a smaller lateral canal and missing anterior and posterior canals (Acampora et al 1999b;Depew et al 1999). The three cristae are malformed, and the two maculae are also reduced in size (Merlo et al 2002).…”

Molecular Conservation and Novelties in Vertebrate Ear Development

“…How GATA3 interacts with FGFs (Pauley et al, 2003;Pirvola et al, 2000), Nkx (Hadrys et al, 1998), Dlx (Merlo et al, 2002;Solomon and Fritz, 2002), forkheads (Solomon et al, 2003), and other genes involved in early ear histogenesis and morphogenesis (Chang et al, 2002;Fekete and Wu, 2002;Xu et al, 1999) is still uncertain (see Chapter 5 by Bober et al and Chapter 8 by Wright and Mansour for additional details). However, multiple binding sites for GATA factors in the promoter regions of forkhead genes have been described (David et al, 1999) and are suggestive that GATA3 is part of a morphostatic cascade in the ear.…”