刺猬信号通路控制神经祖细胞和诱导多能干细胞中的星状微管和有丝分裂纺锤体方向。

Hedgehog signaling controls astral microtubules and mitotic spindle orientation in neural progenitors and iPSCs.

作者信息

Liu Fengming, Medyukhina Anna, Olesen Kris M, Shirinifard Abbas, Jin Hongjian, Li Lei, Mapelli Marina, Khairy Khaled, Han Young-Goo

机构信息

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, United States.

Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, United States.

出版信息

Front Cell Dev Biol. 2025 Jun 6;13:1582924. doi: 10.3389/fcell.2025.1582924. eCollection 2025.

Abstract

Mitotic spindle orientation is crucial for cell fate determination and tissue organization. Although the intracellular machinery governing spindle orientation is well characterized, whether and how secreted factors, such as morphogens, regulate this process remains poorly understood. This study investigated the role of Hedgehog (HH) signaling in modulating mitotic spindle orientation in neural progenitor cells and in induced pluripotent stem cells (iPSCs). Time-lapse microscopy of cerebral organoids and iPSCs revealed that HH signaling increases the angle of the mitotic spindle relative to the apical surface, prolongs mitosis, and enhances spindle rotation. Mechanistically, HH signaling reduces both the number and the length of astral microtubules, key regulators of spindle orientation. This reduction correlates with increased spindle angle in iPSCs. Furthermore, we show that canonical HH signaling, involving GLI-dependent transcriptional regulation, contributes to these effects. RNA sequencing and gene set enrichment analysis (GSEA) revealed that HH signaling upregulates genes associated with microtubule depolymerization, suggesting a transcriptional mechanism by which HH signaling influences astral microtubule dynamics and, consequently, mitotic spindle orientation. These findings highlight a novel link between a morphogen, transcriptional regulation, and the control of mitotic spindle orientation, with implications for development and tissue homeostasis.

摘要

有丝分裂纺锤体定向对于细胞命运决定和组织构建至关重要。尽管调控纺锤体定向的细胞内机制已得到充分表征,但诸如形态发生素等分泌因子是否以及如何调节这一过程仍知之甚少。本研究调查了刺猬信号通路(HH信号通路)在调节神经祖细胞和诱导多能干细胞(iPSC)中有丝分裂纺锤体定向中的作用。对类脑器官和iPSC进行的延时显微镜观察显示,HH信号通路增加了有丝分裂纺锤体相对于顶端表面的角度,延长了有丝分裂,并增强了纺锤体旋转。从机制上讲,HH信号通路减少了星状微管的数量和长度,而星状微管是纺锤体定向的关键调节因子。这种减少与iPSC中纺锤体角度的增加相关。此外,我们表明,涉及GLI依赖的转录调控的经典HH信号通路促成了这些效应。RNA测序和基因集富集分析(GSEA)显示,HH信号通路上调了与微管解聚相关的基因,这表明HH信号通路影响星状微管动力学进而影响有丝分裂纺锤体定向的一种转录机制。这些发现突出了形态发生素、转录调控与有丝分裂纺锤体定向控制之间的新联系,对发育和组织稳态具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e202/12179144/9567b88573be/fcell-13-1582924-g001.jpg

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