Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Science. 2009 Dec 4;326(5958):1424-7. doi: 10.1126/science.1181453.
Granule neuron precursors (GNPs) are the most actively proliferating cells in the postnatal nervous system, and mutations in pathways that control the GNP cell cycle can result in medulloblastoma. The transcription factor Atoh1 has been suspected to contribute to GNP proliferation, but its role in normal and neoplastic postnatal cerebellar development remains unexplored. We show that Atoh1 regulates the signal transduction pathway of Sonic Hedgehog, an extracellular factor that is essential for GNP proliferation, and demonstrate that deletion of Atoh1 prevents cerebellar neoplasia in a mouse model of medulloblastoma. Our data shed light on the function of Atoh1 in postnatal cerebellar development and identify a new mechanism that can be targeted to regulate medulloblastoma formation.
颗粒神经元前体细胞 (GNPs) 是出生后神经系统中最活跃增殖的细胞，控制 GNPs 细胞周期的途径中的突变可导致成神经管细胞瘤。转录因子 Atoh1 被怀疑有助于 GNPs 的增殖，但它在正常和肿瘤性出生后小脑发育中的作用仍未被探索。我们表明，Atoh1 调节 Sonic Hedgehog 的信号转导途径，后者是促进 GNPs 增殖的必需的细胞外因子，并证明 Atoh1 的缺失可防止成神经管细胞瘤小鼠模型中的小脑肿瘤形成。我们的数据阐明了 Atoh1 在出生后小脑发育中的功能，并确定了一种可用于调节成神经管细胞瘤形成的新机制。
