Mouse Hoxa2 mutations provide a model for microtia and auricle duplication

Abstract

SUMMARYExternal ear abnormalities are frequent in newborns ranging from microtia to partial auricle duplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtia associated with an abnormal shape of the auricle. In mice, Hoxa2 inactivation at early gestational stages results in external auditory canal (EAC) duplication and absence of the auricle, whereas its late inactivation results in a hypomorphic auricle, mimicking the human HOXA2 mutant condition. By genetic fate mapping we found that the mouse auricle (or pinna) derives from the Hoxa2-expressing neural crest-derived mesenchyme of the second pharyngeal arch, and not from a composite of first and second arch mesenchyme as previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2-negative first arch mesenchyme and does not develop at the first pharyngeal cleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crest is sufficient to induce a complete duplication of the pinna and a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchyme lining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesis of the pinna through the BMP signalling pathway and expression of Eya1, which in humans is involved in branchio-oto-renal syndrome. Thus, Hoxa2 loss-and gain-of-function approaches in mice provide a suitable model to investigate the molecular aetiology of microtia and auricle duplication.

The genetics of auricular development and malformation: New findings in model systems driving future directions for microtia research

“…The revised model of auricular morphogenesis (Figure 1a) also accommodates exciting new molecular genetic findings in mice reported by Minoux and colleagues (2013). These researchers extended their earlier studies by further characterizing mice deficient for Hoxa2 , that presented as a model for anotia.…”

External ear microRNA expression profiles during mouse development

“…Zeb1 and Zeb2 encode transcription factors that are involved in neural development and in the development of tissues derived from neural crest cells (Shin et al, 2012). Tob1 may negatively regulate the BMP/Smad signaling pathway in osteoblasts, a signaling pathway that has also been implicated in external ear development of early stage mice (Yoshida et al, 2000;Minoux et al, 2013) We found mRNA of Tob1 in pinnae (Fig. 4), but the interaction with mmu-miR-200c, mmu-miR-205 and mmu-miR-429, their possible regulators, is still unknown.…”

“…ear are incompletely understood (Minoux et al, 2013;Luquetti et al, 2012). Recent reports suggest that embryonic development in mammals is accompanied by dynamic changes in the expression of an extensive class of regulatory molecules termed miRNAs (Lau et al, 2001;Berezikov, 2011); therefore, these molecules could be influencing the external ear development process.…”

A distal 594bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by Hox-Pbx-Meis

“…Indeed, Hoxa2, Pbx1 and their binding partners, the Meis proteins, all share overlapping expression domains with Hmx1 in the craniofacial mesenchyme of BA1 and BA2 during development (Amin et al, 2015), and knockout of each results in a more severe ear malformation than that seen in the dumbo mice (Minoux et al, 2013;N.B. and T.C.C., unpublished).…”