Abstract
SUMMARYHmx1 is a homeodomain transcription factor expressed in the developing eye, peripheral ganglia, and branchial arches of avian and mammalian embryos. Recent studies have identified a loss-of-function allele at the HMX1 locus as the causative mutation in the oculo-auricular syndrome (OAS) in humans, characterized by ear and eye malformations. The mouse dumbo (dmbo) mutation, with similar effects on ear and eye development, also results from a loss-of-function mutation in the Hmx1 gene. A recessive dmbo mutation causing ear malformation in rats has been mapped to the chromosomal region containing the Hmx1 gene, but the nature of the causative allele is unknown. Here we show that dumbo rats and mice exhibit similar neonatal ear and eye phenotypes. In midgestation embryos, dumbo rats show a specific loss of Hmx1 expression in neural-crest-derived craniofacial mesenchyme (CM), whereas Hmx1 is expressed normally in retinal progenitors, sensory ganglia and in CM, which is derived from mesoderm. High-throughput resequencing of 1 Mb of rat chromosome 14 from dmbo/dmbo rats, encompassing the Hmx1 locus, reveals numerous divergences from the rat genomic reference sequence, but no coding changes in Hmx1. Fine genetic mapping narrows the dmbo critical region to an interval of ∼410 kb immediately downstream of the Hmx1 transcription unit. Further sequence analysis of this region reveals a 5777-bp deletion located ∼80 kb downstream in dmbo/dmbo rats that is not apparent in 137 other rat strains. The dmbo deletion region contains a highly conserved domain of ∼500 bp, which is a candidate distal enhancer and which exhibits a similar relationship to Hmx genes in all vertebrate species for which data are available. We conclude that the rat dumbo phenotype is likely to result from loss of function of an ultraconserved enhancer specifically regulating Hmx1 expression in neural-crest-derived CM. Dysregulation of Hmx1 expression is thus a candidate mechanism for congenital ear malformation, most cases of which remain unexplained.
Highlights
Hmx1 is a homeodomain transcription factor expressed in the developing eye, peripheral ganglia and branchial arches of avian and mammalian embryos (Wang et al, 2000; Yoshiura et al, 1998)
Our results show that neonatal dumbo rats have a similar phenotype to that observed in dumbo mice, with characteristic ventral displacement of the ear and a moderate degree of microphthalmia
Dumbo rats show a specific loss of Hmx1 expression in neural-crest-derived craniofacial mesenchyme, the maxillary component and most of the mandibular component of the first branchial arch, and the distal part of the second branchial arch
Summary
Hmx is a homeodomain transcription factor expressed in the developing eye, peripheral ganglia and branchial arches of avian and mammalian embryos (Wang et al, 2000; Yoshiura et al, 1998). Patients with OAS exhibit malformations of the outer ear (pinna) and defects of the eye, including microphthalmia, cataract, coloboma and retinal dystrophy (Schorderet et al, 2008; Vaclavik et al, 2011). Animal models of OAS include the dumbo (dmbo) and misplaced ears (mpe) mutations in mice (Munroe et al, 2009). Mouse mpe and the known human Hmx allele causing OAS are all coding mutations that affect the Hmx DNA-binding homeodomain, and are predicted to result in loss of function. In addition to malformed ears, dumbo mice exhibit eye malformations, less severe than those observed in the OAS patients identified to date. In both mouse and man, hearing is spared. The dumbo (dmbo) trait identified in animals kept by amateur ‘fancy rat’ breeders has been mapped to a 5 Mb region encompassing the Hmx locus (Kuramoto et al, 2010), but the nature of the causative mutation is unknown
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