Mouse Hoxa2 mutations provide a model for microtia and auricle duplication.

External ear abnormalities are frequent in newborns ranging from microtiato partial auricleduplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtiaassociated 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 mappingwe found that the mouse auricle(or pinna) derives from the Hoxa2 -expressing neural crest-derived mesenchymeof the second pharyngeal arch, and not from a composite of first and second arch mesenchymeas previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2 -negative first arch mesenchymeand does not develop at the first pharyngealcleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crestis sufficient to induce a complete duplication of the pinnaand a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchymelining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesisof the pinnathrough 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 modelto investigate the molecular aetiology of microtiaand auricleduplication.