Dlx genes pattern mammalian jaw primordium by regulating both lower jaw-specific and upper jaw-specific genetic programs.
Dlx genes pattern mammalian jaw primordium by regulating both lower jaw-specific and upper jaw-specific genetic programs.
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DOI：
10.1242/dev.019778
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发表时间：
2008-09
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影响因子：
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通讯作者：
Rubenstein JL
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文献类型：
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作者：
Jeong J;Li X;McEvilly RJ;Rosenfeld MG;Lufkin T;Rubenstein JL
Dlx转录因子与哺乳动物颌骨的模式有关，基于它们在第一鳃弓（颌骨原基）和突变表型中的嵌套表达模式; Dlx 1和Dlx 2（Dlx 1/2−/−）的失活导致上颌的缺陷，而Dlx 5/6−/−导致下颌向上颌的同源异型转化。因此，“Dlx代码”似乎区域化颌骨原基，Dlx 1/2调节上颌发育，而Dlx 5/6赋予下颌的命运。为了确定Dlx 5/6下游的遗传途径，我们比较了野生型和Dlx 5/6−/−小鼠下颌弓（预期下颌）的基因表达谱。我们确定了20个以前未识别的Dlx 5/6下游基因，其中12个下调，8个上调的突变体。我们发现了一个Dlx调节的转录增强子，与Dlx 5/6下游基因之一Gbx 2非常接近，这强烈表明Gbx 2是Dlx 5/6的直接靶点。我们还发现，Pou 3f 3通常在上颌（预期的上颌）而不是下颌弓中表达，在Dlx 5/6−/−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。各种DLX单和双突变体的形态和分子表型的比较分析表明，DLX 1，2，5和6的行为都部分冗余和拮抗性，直接差异表达的下游基因在每个域的第一鳃arch. We提出了一个新的模型DLX介导的哺乳动物颌骨图案。
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.