Calcium dynamics at the neural cell primary cilium regulate Hedgehog signaling-dependent neurogenesis in the embryonic neural tube.
Calcium dynamics at the neural cell primary cilium regulate Hedgehog signaling-dependent neurogenesis in the embryonic neural tube.
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神经细胞初级纤毛的钙动力学调节胚胎神经管中Hedgehog信号依赖的神经发生。
DOI：
10.1073/pnas.2220037120
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发表时间：
2023-06-06
影响因子：
11.1
通讯作者：
Borodinsky, Laura N.
中科院分区：
文献类型：
--
作者：
Shim, Sangwoo;Goyal, Raman;Panoutsopoulos, Alexios A.;Balashova, Olga A.;Lee, David;Borodinsky, Laura N.
发育过程中神经细胞增殖和神经元分化之间的不平衡可能导致儿科癌症或神经发育障碍。因此，了解控制这种转变的机制对于预防和治疗这些疾病至关重要。在这里，我们展示了在发育中的神经细胞初级纤毛中钙依赖机制的招募，将发育信号Sonic Headgehog从增殖转化为分化。已知的机制可能成为设计脑肿瘤治疗药物的靶点。神经干细胞增殖和神经元分化之间的平衡对于神经系统的正常发育至关重要。Sonic hedgehog(Shh)具有促进细胞增殖和指定神经元表型的作用，但促进细胞从有丝分裂向神经源性转化的信号机制尚不清楚。在这里，我们发现Shh通过瞬时受体势阳离子通道C亚家族成员3(TRPC3)的钙离子内流和细胞内钙释放，以一种发育阶段依赖的方式增强非洲爪哇胚胎神经细胞初级纤毛上的钙离子活性。这种纤毛钙的活性反过来通过下调Sox2的表达和上调神经源性基因的表达来拮抗神经干细胞中规范的、增殖的Shh信号，从而使神经元分化。这些发现表明，神经细胞纤毛信号中的Shh-Ca~(2+)依赖的开关触发了Shh作用从标准有丝分裂到神经源性的切换。在这个神经源性信号轴中发现的分子机制是治疗脑肿瘤和神经发育障碍的潜在靶点。
Imbalance between neural cell proliferation and neuronal differentiation during development can result in pediatric cancer or neurodevelopmental disorders. Thus, understanding the mechanisms that control this transition is paramount for preventing and treating these conditions. Here we show that the recruitment of a calcium-dependent mechanism in the developing neural cell primary cilium, converts the developmental signal Sonic hedgehog from proliferative into differentiating. The identified mechanism may become a target for devising therapeutics for brain tumors. The balance between neural stem cell proliferation and neuronal differentiation is paramount for the appropriate development of the nervous system. Sonic hedgehog (Shh) is known to sequentially promote cell proliferation and specification of neuronal phenotypes, but the signaling mechanisms responsible for the developmental switch from mitogenic to neurogenic have remained unclear. Here, we show that Shh enhances Ca2+ activity at the neural cell primary cilium of developing Xenopus laevis embryos through Ca2+ influx via transient receptor potential cation channel subfamily C member 3 (TRPC3) and release from intracellular stores in a developmental stage-dependent manner. This ciliary Ca2+ activity in turn antagonizes canonical, proliferative Shh signaling in neural stem cells by down-regulating Sox2 expression and up-regulating expression of neurogenic genes, enabling neuronal differentiation. These discoveries indicate that the Shh-Ca2+-dependent switch in neural cell ciliary signaling triggers the switch in Shh action from canonical-mitogenic to neurogenic. The molecular mechanisms identified in this neurogenic signaling axis are potential targets for the treatment of brain tumors and neurodevelopmental disorders.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.6
作者：
Balashova, Olga A.;Visina, Olesya;Borodinsky, Laura N.
通讯作者：
Borodinsky, Laura N.
影响因子：
8.8
作者：
Hagey, Daniel W.;Muhr, Jonas
通讯作者：
Muhr, Jonas
影响因子：
25
作者：
Favaro, Rebecca;Valotta, Menella;Nicolis, Silvia K.
通讯作者：
Nicolis, Silvia K.
影响因子：
64.8
作者：
Borodinsky, LN;Root, CM;Spitzer, NC
通讯作者：
Spitzer, NC