The role ofSix1in mammalian auditory system development

Abstract

The homeobox Six genes, homologues to Drosophila sine oculis(so) gene, are expressed in multiple organs during mammalian development. However, their roles during auditory system development have not been studied. We report that Six1 is required for mouse auditory system development. During inner ear development, Six1 expression was first detected in the ventral region of the otic pit and later is restricted to the middle and ventral otic vesicle within which, respectively, the vestibular and auditory epithelia form. By contrast, Six1 expression is excluded from the dorsal otic vesicle within which the semicircular canals form. Six1 is also expressed in the vestibuloacoustic ganglion. At E15.5, Six1 is expressed in all sensory epithelia of the inner ear. Using recently generated Six1 mutant mice, we found that all Six1+/- mice showed some degree of hearing loss because of a failure of sound transmission in the middle ear. By contrast, Six1-/- mice displayed malformations of the auditory system involving the outer, middle and inner ears. The inner ear development in Six1-/- embryos arrested at the otic vesicle stage and all components of the inner ear failed to form due to increased cell death and reduced cell proliferation in the otic epithelium. Because we previously reported that Six1 expression in the otic vesicle is Eya1dependent, we first clarified that Eya1 expression was unaffected in Six1-/- otic vesicle, further demonstrating that the Drosophila Eya-Six regulatory cassette is evolutionarily conserved during mammalian inner ear development. We also analyzed several other otic markers and found that the expression of Pax2 and Pax8 was unaffected in Six1-/- otic vesicle. By contrast, Six1 is required for the activation of Fgf3 expression and the maintenance of Fgf10 and Bmp4 expression in the otic vesicle. Furthermore, loss of Six1 function alters the expression pattern of Nkx5.1 and Gata3, indicating that Six1is required for regional specification of the otic vesicle. Finally, our data suggest that the interaction between Eya1 and Six1 is crucial for the morphogenesis of the cochlea and the posterior ampulla during inner ear development. These analyses establish a role for Six1 in early growth and patterning of the otic vesicle.

Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

“…Indeed, our previous studies in tissue culture cells have demonstrated that Six1 overexpression can alter progression through S phase and also through G 2 /M (Ford et al, 1998;Coletta et al, 2004), times when Six1 activity would be expected to be high. Furthermore, a number of knockout studies in mice have demonstrated a critical role for Six1 in the proliferation of precursor cell populations, leaving no ambiguity about the importance of Six1 in proliferation in vivo (Zheng et al, 2003;Ozaki et al, 2004).…”

“…(Li et al, 2003;Zheng et al, 2003;Ozaki et al, 2004). Gene amplification and overexpression of Six1 is observed in human cancers, where it confers developmental properties on adult cells leading to an increase in both proliferation and metastasis (Li et al, 2002;Coletta et al, 2004;Reichenberger et al, 2005;Yu et al, 2006).…”

Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only geneegl-1inCaenorhabditis elegans

“…Mutations in SIX1 and EYA1 were identified in human patients with branchio-oto-renal (BOR) syndrome, which is characterized by craniofacial abnormalities, hearing loss, and kidney defects (39,40). Six1-or Eya1-deficient mice showed increased apoptosis in the inner ear and kidney, likely causing a lack of inner ear structure and failure of kidney development (32,42,43). In these mice, increased or decreased apoptosis is seen in tissues in which abnormalities also are observed in human HPE or BOR patients.…”

Redéploiement des gènes Six au cours de l’évolution

“…L'analyse des marqueurs myogéniques exprimés chez ces souris a permis d'établir le rôle tardif de Six1 au cours de la myogenèse primaire (Figure 2). Six1 participe également à l'organogenèse rénale et thymique, à la morphogenèse du squelette craniofacial et thoracique, ainsi qu'à la différenciation de l'oreille interne, de la cavité nasale et des glandes lacrymales et parotides [27][28][29][30]. Comme la plupart de ces défauts sont comparables à ceux décrits chez les souris dont le gène Eya1 a été invalidé (Figure 3) [31,32], il est probable que Six1 et Eya1 agissent en synergie pour induire le développement de ces organes selon un mécanisme similaire à celui mis en évidence chez la drosophile au cours de l'organogenèse oculaire.…”