title: HOXA13 regulates Aldh1a2 expression in the autopod to facilitate interdigital programmed cell death.
abstract: BACKGROUND
  Retinoic acid (RA), plays an essential role in the growth and patterning of vertebrate limb. While the developmental processes regulated by RA are well understood, little is known about the transcriptional mechanisms required to precisely control limb RA synthesis. Here, Aldh1a2 functions as the primary enzyme necessary for RA production which regulates forelimb outgrowth and hindlimb digit separation. Because mice lacking HOXA13 exhibit similar defects in digit separation as Aldh1a2 mutants, we hypothesized that HOXA13 regulates Aldh1a2 to facilitate RA-mediated interdigital programmed cell death (IPCD) and digit separation.
  
  
  RESULTS
  In this report, we identify Aldh1a2 as a direct target of HOXA13. In absence of HOXA13 function, Aldh1a2 expression, RA signaling, and IPCD are reduced. In the limb, HOXA13 binds a conserved cis-regulatory element in the Aldh1a2 locus that can be regulated by HOXA13 to promote gene expression. Finally, decreased RA signaling and IPCD can be partially rescued in the Hoxa13 mutant hindlimb by maternal RA supplementation.
  
  
  CONCLUSIONS
  Defects in IPCD and digit separation in Hoxa13 mutant mice may be caused in part by reduced levels of RA signaling stemming from a loss in the direct regulation of Aldh1a2. These findings provide new insights into the transcriptional regulation of RA signaling necessary for limb morphogenesis.
authors.affiliation: University of Chicago Microarray Core, Room G405, Hospital Building MC5100, Chicago, Illinois, USA.
authors.forename: Siming
authors.initials: S
authors.lastname: Shou
authors.forename: Hanqian L
authors.initials: HL
authors.lastname: Carlson
authors.forename: Wilma D
authors.initials: WD
authors.lastname: Perez
authors.forename: H Scott
authors.initials: HS
authors.lastname: Stadler
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D019521:Body Patterning; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D050697:Retinal Dehydrogenase; D000072516:Retinoic Acid 4-Hydroxylase; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes; D014212:Tretinoin / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C099959:homeobox protein HOXA13; D049452:Green Fluorescent Proteins; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase