Jeong Juhee, Li Xue, McEvilly Robert J, Rosenfeld Michael G, Lufkin Thomas, Rubenstein John L R
Department of Psychiatry, Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, 1550 4th street, San Francisco, CA 94158, USA.
Development. 2008 Sep;135(17):2905-16. doi: 10.1242/dev.019778.
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.
基于Dlx转录因子在第一鳃弓（颌骨原基）中的嵌套表达模式和突变体表型，它们与哺乳动物颌骨的模式形成有关；Dlx1和Dlx2（Dlx1/2-/-）失活会导致上颌骨出现缺陷，而Dlx5/6（-/-）则会导致下颌骨向上颌骨的同源转化。因此，“Dlx编码”似乎使颌骨原基区域化，使得Dlx1/2调节上颌骨发育，而Dlx5/6赋予下颌骨命运。为了确定Dlx5/6下游的遗传途径，我们比较了野生型和Dlx5/6（-/-）小鼠下颌弓（预期的下颌骨）的基因表达谱。我们鉴定出20个以前未被识别的Dlx5/6下游基因，其中12个在突变体中下调，8个上调。我们在Dlx5/6下游基因之一Gbx2附近发现了一个Dlx调节的转录增强子，强烈表明Gbx2是Dlx5/6的直接靶标。我们还表明，Pou3f3通常在上颌骨（预期的上颌骨）而非下颌弓中表达，在Dlx5/6（-/-）的下颌弓中上调，并且对于一些上颌弓衍生骨骼的形成至关重要。对各种Dlx单突变体和双突变体的形态和分子表型的比较分析表明，Dlx1、2、5和6在第一鳃弓的每个区域中对下游基因的直接差异表达既有部分冗余作用，又有拮抗作用。我们提出了一种新的Dlx介导的哺乳动物颌骨模式形成模型。
