Graf Martin, Teo Qi-Wen Elizabeth-Raye, Sarusie Menachem Viktor, Rajaei Flora, Winkler Christoph
Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore 117543.
Mol Endocrinol. 2015 Feb;29(2):187-99. doi: 10.1210/me.2014-1176. Epub 2014 Dec 9.
Dmrt transcription factors control sex determination or sex-specific differentiation across all invertebrate and vertebrate species, in which they have been studied so far. In addition to important functions in the reproductive system, also nongonadal roles have been assigned to several dmrt family members. One example is dmrt5, which was shown to guide neurogenesis in the forebrain of some vertebrates including fish. Here we show that in zebrafish, dmrt5 is also expressed adjacent to the pituitary anlage and later in the anterior pars distalis in which it organizes differentiation of endocrine cells. We find that pituitary induction, cell survival, proliferation, and early lineage specification in the pituitary is independent of dmrt5. Instead, dmrt5 is required for terminal differentiation of corticotropes and gonadotropes. Gene knockdown and mutant analysis revealed that dmrt5 promotes corticotrope differentiation via tbx19 expression, whereas it prevents gonadotrope differentiation in the anterior pars distalis. In dmrt5 morphants and mutants, reduced corticotrope numbers may result in irregular positioning and reduced maintenance of lactotropes. In conclusion, our study establishes a novel function for dmrt5 for cell differentiation in the anterior pituitary. Intriguingly, its effect on gonadotrope numbers defines a first nongonadal role for a dmrt family member that appears crucial for the activity of the reproductive system.
Dmrt转录因子在迄今为止已被研究的所有无脊椎动物和脊椎动物物种中控制性别决定或性别特异性分化。除了在生殖系统中具有重要功能外，几个Dmrt家族成员还被赋予了非性腺功能。一个例子是Dmrt5，它被证明在包括鱼类在内的一些脊椎动物的前脑神经元生成中起引导作用。在这里我们表明，在斑马鱼中，Dmrt5也在垂体原基附近表达，随后在前叶远侧部表达，在那里它组织内分泌细胞的分化。我们发现垂体的诱导、细胞存活、增殖和早期谱系特化不依赖于Dmrt5。相反，Dmrt5是促肾上腺皮质激素细胞和促性腺激素细胞终末分化所必需的。基因敲低和突变分析表明，Dmrt5通过tbx19表达促进促肾上腺皮质激素细胞分化，而它在前叶远侧部阻止促性腺激素细胞分化。在Dmrt5 morphants和突变体中，促肾上腺皮质激素细胞数量减少可能导致催乳素细胞定位不规则和维持减少。总之，我们的研究确立了Dmrt5在垂体前叶细胞分化中的新功能。有趣的是，它对促性腺激素细胞数量的影响定义了Dmrt家族成员在非性腺方面的首个作用，这似乎对生殖系统的活动至关重要。
