Dlx genes pattern mammalian jaw primordium by regulating both lower jaw-specific and upper jaw-specific genetic programs.
Dlx transcription factors are implicated in patterning the mammalian jaw, based on their nested expression patterns in the first branchial arch (primordium for jaw) and mutant phenotypes; inactivation of Dlx1 and Dlx2 (Dlx1/2-/-) causes defects in the upper jaw, whereas Dlx5/6(-/-) results in homeotic transformation of the lower jaw into upper jaw. Therefore, the 'Dlx codes' appear to regionalize the jaw primordium such that Dlx1/2 regulate upper jaw development, while Dlx5/6 confer the lower jaw fate. Towards identifying the genetic pathways downstream of Dlx5/6, we compared the gene expression profiles of the wild-type and Dlx5/6(-/-) mouse mandibular arch (prospective lower jaw). We identified 20 previously unrecognized Dlx5/6-downstream genes, of which 12 were downregulated and 8 upregulated in the mutant. We found a Dlx-regulated transcriptional enhancer in close proximity to Gbx2, one of the Dlx5/6-downstream genes, strongly suggesting that Gbx2 is a direct target of Dlx5/6. We also showed that Pou3f3 is normally expressed in the maxillary (prospective upper jaw) but not mandibular arch, is upregulated in the mandibular arch of Dlx5/6(-/-), and is essential for formation of some of the maxillary arch-derived skeleton. A comparative analysis of the morphological and molecular phenotypes of various Dlx single and double mutants revealed that Dlx1, 2, 5 and 6 act both partially redundantly and antagonistically to direct differential expression of downstream genes in each domain of the first branchial arch. We propose a new model for Dlx-mediated mammalian jaw patterning.
Jeong
Juhee
J
Department of Psychiatry, Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, 1550 4th street, San Francisco, CA 94158, USA. juhee.jeong@ucsf.edu
Li
Xue
X
McEvilly
Robert J
RJ
Rosenfeld
Michael G
MG
Lufkin
Thomas
T
Rubenstein
John L R
JL
D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics*; D001934:Branchial Region / Q000166:cytology / Q000196:embryology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007568:Jaw / Q000196:embryology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
C088334:Distal-less homeobox proteins; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; C513182:Gbx2 protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D050809:POU Domain Factors; D012333:RNA, Messenger; D022661:RNA, Untranslated; D012097:Repressor Proteins; D014157:Transcription Factors; C074065:Pou3f3 protein, mouse