Chojnowski Jena L, Trau Heidi A, Masuda Kyoko, Manley Nancy R
Department of Genetics, Paul D. Coverdell Center, University of Georgia, 500 DW Brooks Drive, Athens, GA, 30602, USA.
Department of Genetics, Paul D. Coverdell Center, University of Georgia, 500 DW Brooks Drive, Athens, GA, 30602, USA.
Dev Biol. 2016 Jul 1;415(1):33-45. doi: 10.1016/j.ydbio.2016.05.010. Epub 2016 May 10.
Hoxa3(null) mice have severe defects in the development of pharyngeal organs including athymia, aparathyroidism, thyroid hypoplasia, and ultimobranchial body persistence, in addition to defects of the throat cartilages and cranial nerves. Some of the structures altered in the Hoxa3(null) mutant embryos are anterior to the described Hoxa3 gene expression boundary: the thyroid, soft palate, and lesser hyoid horn. All of these structures develop over time and through the interactions of multiple cell types. To investigate the specific cellular targets for HOXA3 function in these structures across developmental time, we performed a comprehensive analysis of the temporal and tissue-specific requirements for Hoxa3, including a lineage analysis using Hoxa3(Cre). The combination of these approaches showed that HOXA3 functions in both a cell autonomous and non-cell autonomous manner during development of the 3rd and 4th arch derivatives, and functions in a neural crest cell (NCC)-specific, non-cell autonomous manner for structures that were Hoxa3-negative by lineage tracing. Our data indicate that HOXA3 is required for tissue organization and organ differentiation in endodermal cells (in the tracheal epithelium, thymus, and parathyroid), and contributes to organ migration and morphogenesis in NCCs. These data provide a detailed picture of where and when HOXA3 acts to promote the development of the diverse structures that are altered in the Hoxa3(null) mutant. Data presented here, combined with our previous studies, indicate that the regionally restricted defects in Hoxa3 mutants do not reflect a role in positional identity (establishment of cell or tissue fate), but instead indicate a wider variety of functions including controlling distinct genetic programs for differentiation and morphogenesis in different cell types during development.
Hoxa3基因敲除小鼠在咽器官发育方面存在严重缺陷，包括无胸腺、甲状旁腺功能减退、甲状腺发育不全以及鳃后体持续存在，此外还存在喉软骨和颅神经缺陷。在Hoxa3基因敲除突变胚胎中发生改变的一些结构位于所描述的Hoxa3基因表达边界之前：甲状腺、软腭和小角舌骨。所有这些结构都是随着时间推移并通过多种细胞类型的相互作用而发育形成的。为了研究HOXA3在这些结构发育过程中的特定细胞靶点，我们对Hoxa3的时间和组织特异性需求进行了全面分析，包括使用Hoxa3(Cre)进行谱系分析。这些方法的结合表明，HOXA3在第三和第四鳃弓衍生物的发育过程中以细胞自主和非细胞自主的方式发挥作用，并且对于通过谱系追踪显示为Hoxa3阴性的结构，以神经嵴细胞（NCC）特异性、非细胞自主的方式发挥作用。我们的数据表明，HOXA3是内胚层细胞（气管上皮、胸腺和甲状旁腺）组织组织和器官分化所必需的，并有助于NCCs中的器官迁移和形态发生。这些数据详细描绘了HOXA3在何时何地发挥作用以促进Hoxa3基因敲除突变体中发生改变的各种结构的发育。此处呈现的数据与我们之前的研究相结合，表明Hoxa3突变体中区域受限的缺陷并不反映其在位置身份（细胞或组织命运的确定）中的作用，而是表明其具有更广泛的功能，包括在发育过程中控制不同细胞类型中分化和形态发生的不同遗传程序。
