A distal 594 bp ECR specifies Hmx1 expression in pinna and lateral facial morphogenesis and is regulated by the Hox-Pbx-Meis complex.
Hmx1 encodes a homeodomain transcription factor expressed in the developing lateral craniofacial mesenchyme, retina and sensory ganglia. Mutation or mis-regulation of Hmx1 underlies malformations of the eye and external ear in multiple species. Deletion or insertional duplication of an evolutionarily conserved region (ECR) downstream of Hmx1 has recently been described in rat and cow, respectively. Here, we demonstrate that the impact of Hmx1 loss is greater than previously appreciated, with a variety of lateral cranioskeletal defects, auriculofacial nerve deficits, and duplication of the caudal region of the external ear. Using a transgenic approach, we demonstrate that a 594 bp sequence encompassing the ECR recapitulates specific aspects of the endogenous Hmx1 lateral facial expression pattern. Moreover, we show that Hoxa2, Meis and Pbx proteins act cooperatively on the ECR, via a core 32 bp sequence, to regulate Hmx1 expression. These studies highlight the conserved role for Hmx1 in BA2-derived tissues and provide an entry point for improved understanding of the causes of the frequent lateral facial birth defects in humans.
Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Jessica M
JM
Rosin
Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA Department of Oral Health Sciences, University of Washington, Seattle, WA 98195, USA.
Wenjie
W
Li
Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA Department of Pediatrics (Craniofacial Medicine), University of Washington, Seattle, WA 98195, USA.
Liza L
0000-0002-0703-7258
LL
Cox
Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Sara M
SM
Rolfe
School of Dentistry, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, UK.
Victor
V
Latorre
Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Jennifer A
0000-0002-0667-9355
JA
Akiyama
Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA DOE Joint Genome Institute, Walnut Creek, CA 94598, USA School of Natural Sciences, University of California, Merced, CA 95343, USA.
Axel
0000-0002-4130-7784
A
Visel
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Takashi
T
Kuramoto
School of Dentistry, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, UK.
Nicoletta
0000-0002-7103-4932
N
Bobola
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Eric E
0000-0001-5499-6788
EE
Turner
Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA Department of Oral Health Sciences, University of Washington, Seattle, WA 98195, USA Department of Pediatrics (Craniofacial Medicine), University of Washington, Seattle, WA 98195, USA Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia tccox@uw.edu.
Timothy C
0000-0001-8015-5528
TC
Cox
D000818:Animals; D020029:Base Pairing / Q000235:genetics*; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D054644:Ear Auricle / Q000002:abnormalities / Q000378:metabolism* / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D019143:Evolution, Molecular; D005145:Face / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D010812:Physical Stimulation; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding / Q000235:genetics; D011984:Sensory Receptor Cells / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D018398:Homeodomain Proteins; C489833:Hoxa2 protein, mouse; C102641:Mrg1 protein, mouse; C529125:NKX5-3 protein, mouse; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors
Craniofacial mesenchyme; Enhancer; Evolutionarily conserved region (ECR); Hmx1; Mouse; Pinna