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Title: 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. In conclusion, 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.
Authors:
 [1] ;  [2] ; ORCiD logo [2] ;  [1] ;  [3] ; ORCiD logo [4] ; ORCiD logo [5] ;  [6] ; ORCiD logo [3] ; ORCiD logo [2] ; ORCiD logo [7]
  1. Seattle Children's Research Institute, Seattle, WA (United States)
  2. Seattle Children's Research Institute, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States)
  3. Univ. of Manchester, Manchester (United Kingdom)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States)
  6. Kyoto Univ., Kyoto (Japan)
  7. Seattle Children's Research Institute, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States); Monash Univ., Clayton, VIC (Australia)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Development (Cambridge)
Additional Journal Information:
Journal Name: Development (Cambridge); Journal Volume: 143; Journal Issue: 14; Journal ID: ISSN 0950-1991
Publisher:
Company of Biologists
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Hmx1; Evolutionarily conserved region (ECR); Enhancer; Craniofacial mesenchyme; Pinna; Mouse
OSTI Identifier:
1393060