Mani Shyamala, Radhakrishnan Saranya, Cheramangalam Rajit Narayanan, Harkar Shalini, Rajendran Samyutha, Ramanan Narendrakumar
Centre for Neuroscience, Indian Institute of Science, Bengaluru, 560012, India.
Curadev Pharma, Pvt. Ltd., B-87, Sector 83, Noida, Uttar Pradesh, 201305, India.
Cerebellum. 2020 Oct;19(5):645-664. doi: 10.1007/s12311-020-01138-2.
Cerebellar granule neuron progenitors (CGNPs) give rise to the cerebellar granule neurons in the developing cerebellum. Generation of large number of these neurons is made possible by the high proliferation rate of CGNPs in the external granule layer (EGL) in the dorsal cerebellum. Here, we show that upregulation of β-catenin can maintain murine CGNPs in a state of proliferation. Further, we show that β-catenin mRNA and protein levels can be regulated by the mitogen Sonic hedgehog (Shh). Shh signaling led to an increase in the level of the transcription factor N-myc. N-myc was found to bind the β-catenin promoter, and the increase in β-catenin mRNA and protein levels could be prevented by blocking N-myc upregulation downstream of Shh signaling. Furthermore, blocking Wingless-type MMTV integration site (Wnt) signaling by Wnt signaling pathway inhibitor Dickkopf 1 (Dkk-1) in the presence of Shh did not prevent the upregulation of β-catenin. We propose that in culture, Shh signaling regulates β-catenin expression through N-myc and results in increased CGNP proliferation.
小脑颗粒神经元前体细胞（CGNPs）在发育中的小脑中产生小脑颗粒神经元。背侧小脑外颗粒层（EGL）中CGNPs的高增殖率使得大量这些神经元的产生成为可能。在此，我们表明β-连环蛋白的上调可使小鼠CGNPs维持在增殖状态。此外，我们表明β-连环蛋白的mRNA和蛋白质水平可受有丝分裂原音猬因子（Shh）调节。Shh信号传导导致转录因子N-myc水平升高。发现N-myc结合β-连环蛋白启动子，并且通过阻断Shh信号传导下游的N-myc上调可防止β-连环蛋白mRNA和蛋白质水平的升高。此外，在存在Shh的情况下，通过Wnt信号通路抑制剂Dickkopf 1（Dkk-1）阻断无翅型MMTV整合位点（Wnt）信号传导并不能阻止β-连环蛋白的上调。我们提出，在培养中，Shh信号传导通过N-myc调节β-连环蛋白表达并导致CGNP增殖增加。
