Department of Cardiology, Manton Center for Orphan Disease, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):E225-33. doi: 10.1073/pnas.1120033109. Epub 2011 Dec 27.
Global disruption of transient receptor potential-melastatin-like 7 (Trpm7) in mice results in embryonic lethality before embryonic day 7. Using tamoxifen-inducible disruption of Trpm7 and multiple Cre recombinase lines, we show that Trpm7 deletion before and during organogenesis results in severe tissue-specific developmental defects. We find that Trpm7 is essential for kidney development from metanephric mesenchyme but not ureteric bud. Disruption of neural crest Trpm7 at early stages results in loss of pigment cells and dorsal root ganglion neurons. In contrast, late disruption of brain-specific Trpm7 after embryonic day 10.5 does not alter normal brain development. We developed induced pluripotent stem cells and neural stem (NS) cells in which Trpm7 disruption could be induced. Trpm7(-/-) NS cells retained the capacities of self-renewal and differentiation into neurons and astrocytes. During in vitro differentiation of induced pluripotent stem cells to NS cells, Trpm7 disruption prevents the formation of the NS cell monolayer. The in vivo and in vitro results demonstrate a temporal requirement for the Trpm7 channel kinase during embryogenesis.
在小鼠中，瞬时受体电位阳离子通道亚家族 M 成员 7（Trpm7）的全球缺失导致胚胎在第 7 天之前死亡。使用他莫昔芬诱导的 Trpm7 缺失和多种 Cre 重组酶系，我们表明在器官发生之前和期间缺失 Trpm7 会导致严重的组织特异性发育缺陷。我们发现 Trpm7 对于从后肾间充质发育的肾脏是必需的，但对于输尿管芽不是必需的。早期破坏神经嵴 Trpm7 会导致色素细胞和背根神经节神经元丢失。相比之下，在胚胎第 10.5 天后晚期破坏大脑特异性 Trpm7 不会改变正常的大脑发育。我们开发了诱导多能干细胞和神经干细胞（NS）细胞，其中可以诱导 Trpm7 缺失。Trpm7（-/-）NS 细胞保留自我更新和分化为神经元和星形胶质细胞的能力。在诱导多能干细胞向 NS 细胞体外分化过程中，Trpm7 缺失阻止了 NS 细胞单层的形成。体内和体外结果表明，Trpm7 通道激酶在胚胎发生过程中具有时间依赖性。
