Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, 10065, United States; Developmental Biology Program, Sloan Kettering Institute, New York, NY, 10065, United States.
Biochemistry, Cell and Molecular Biology Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, 10065, United States; Developmental Biology Program, Sloan Kettering Institute, New York, NY, 10065, United States.
Dev Biol. 2019 Nov 15;455(2):458-472. doi: 10.1016/j.ydbio.2019.07.018. Epub 2019 Jul 31.
The cerebellum undergoes major rapid growth during the third trimester and early neonatal stage in humans, making it vulnerable to injuries in pre-term babies. Experiments in mice have revealed a remarkable ability of the neonatal cerebellum to recover from injuries around birth. In particular, recovery following irradiation-induced ablation of granule cell precursors (GCPs) involves adaptive reprogramming of Nestin-expressing glial progenitors (NEPs). Sonic hedgehog signaling is required for the initial step in NEP reprogramming; however, the full spectrum of developmental signaling pathways that promote NEP-driven regeneration is not known. Since the growth regulatory Hippo pathway has been implicated in the repair of several tissue types, we tested whether Hippo signaling is involved in regeneration of the cerebellum. Using mouse models, we found that the Hippo pathway transcriptional co-activator YAP1 (Yes-associated protein 1) but not TAZ (transcriptional coactivator with PDZ binding motif, or WWTR1) is required in NEPs for full recovery of cerebellar growth following irradiation one day after birth. Although Yap1 plays only a minor role during normal development in differentiation of NEPs or GCPs, the size of the cerebellum, and in particular the internal granule cell layer produced by GCPs, is significantly reduced in Yap1 mutants after irradiation, and the organization of Purkinje cells and Bergmann glial fibers is disrupted. The initial proliferative response of Yap1 mutant NEPs to irradiation is normal and the cells migrate to the GCP niche, but subsequently there is increased cell death of GCPs and altered migration of granule cells, possibly due to defects in Bergmann glia. Moreover, loss of Taz along with Yap1 in NEPs does not abrogate regeneration or alter development of the cerebellum. Our study provides new insights into the molecular signaling underlying postnatal cerebellar development and regeneration.
小脑在人类的第三个孕期和新生儿早期经历了主要的快速生长，使其容易受到早产儿的损伤。在小鼠中的实验揭示了新生小脑在出生时受伤后恢复的惊人能力。特别是，在颗粒细胞前体细胞（GCP）诱导的照射消融后，巢蛋白表达神经胶质前体（NEP）的适应性重编程涉及恢复。Sonic hedgehog 信号对于 NEP 重编程的初始步骤是必需的；然而，促进 NEP 驱动再生的完整发育信号通路谱尚不清楚。由于生长调节 Hippo 途径已被牵连到几种组织类型的修复中，因此我们测试了 Hippo 信号是否参与小脑的再生。使用小鼠模型，我们发现 Hippo 途径转录共激活因子 YAP1（Yes-associated protein 1）而不是 TAZ（具有 PDZ 结合基序的转录共激活因子，或 WWTR1）对于在出生后一天接受照射后，NEPs 中的小脑生长完全恢复是必需的。尽管 Yap1 在 NEPs 或 GCPs 的分化的正常发育中仅发挥次要作用，但在照射后，yap1 突变体中小脑的大小，特别是由 GCP 产生的内部颗粒细胞层，显著减小，并且浦肯野细胞和伯格曼神经胶质纤维的组织被破坏。yap1 突变体 NEPs 对照射的初始增殖反应是正常的，并且细胞迁移到 GCP 生态位，但随后 GCP 细胞死亡增加，并且颗粒细胞迁移改变，可能是由于伯格曼神经胶质的缺陷。此外，NEPs 中 Taz 的缺失以及 Yap1 的缺失并不消除再生或改变小脑的发育。我们的研究为出生后小脑发育和再生的分子信号提供了新的见解。
