Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors
Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors
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DOI：
10.1242/dev.153387
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发表时间：
2017-09-15
期刊：
影响因子：
4.6
通讯作者：
Martinez-Barbera, Juan Pedro
中科院分区：
文献类型：
--
作者：
Carreno, Gabriela;Apps, John R.;Martinez-Barbera, Juan Pedro
Sonic hedgehog(SHH)是一种重要的形态发生信号，它决定了哺乳动物几个发育器官的细胞命运。体外数据表明，SHH需要指定LHX3(+)/LHX4(+)Rathke氏囊(RP)祖细胞的身份。然而，体内研究未能揭示这种功能，相反，支持SHH在促进这些RP前体细胞的增殖和垂体细胞类型分化方面发挥关键作用。在这里，我们使用遗传学的方法来证明SHH通路的激活是诱导小鼠胚胎中LHX3(+)/LHX4(+)RP同一性所必需的。首先，我们发现，在下丘脑前部有条件地缺失Shh会导致完全穿透的表型，其特征是RP发育完全停止，在性交后9.0天(DPC)时RP上皮中缺乏Lhx3/Lhx4的表达，12.5DPC时垂体组织完全丧失。相反，在RP祖细胞中，通过有条件地缺失ptch1而过度激活SHH通路，会导致妊娠结束时Sox2(+)干细胞室的严重增殖和扩大。
Sonic hedgehog (SHH) is an essential morphogenetic signal that dictates cell fate decisions in several developing organs in mammals. In vitro data suggest that SHH is required to specify LHX3(+)/LHX4(+) Rathke's pouch (RP) progenitor identity. However, in vivo studies have failed to reveal such a function, supporting instead a crucial role for SHH in promoting proliferation of these RP progenitors and for differentiation of pituitary cell types. Here, we have used a genetic approach to demonstrate that activation of the SHH pathway is necessary to induce LHX3(+)/LHX4(+) RP identity in mouse embryos. First, we show that conditional deletion of Shh in the anterior hypothalamus results in a fully penetrant phenotype characterised by a complete arrest of RP development, with lack of Lhx3/Lhx4 expression in RP epithelium at 9.0 days post coitum (dpc) and total loss of pituitary tissue by 12.5 dpc. Conversely, overactivation of the SHH pathway by conditional deletion of Ptch1 in RP progenitors leads to severe hyperplasia and enlargement of the Sox2(+) stem cell compartment by the end of gestation.