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A Novel Role of the Mad Family Member Mad3 in Cerebellar Granule Neuron Precursor Proliferation

机译：疯狂家族成员Mad3在小脑颗粒神经元前体增殖中的新型作用。

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During development, Sonic hedgehog (Shh) regulates the proliferation of cerebellar granule neuron precursors (GNPs) in part via expression of Nmyc. We present evidence supporting a novel role for the Mad family member Mad3 in the Shh pathway to regulate Nmyc expression and GNP proliferation. Mad3 mRNA is transiently expressed in GNPs during proliferation. Cultured GNPs express Mad3 in response to Shh stimulation in a cyclopamine-dependent manner. Mad3 is necessary for Shh-dependent GNP proliferation as measured by bromodeoxyuridine incorporation and Nmyc expression. Furthermore, Mad3 overexpression, but not that of other Mad proteins, is sufficient to induce GNP proliferation in the absence of Shh. Structure-function analysis revealed that Max dimerization and recruitment of the mSin3 corepressor are required for Mad3-mediated GNP proliferation. Surprisingly, basic-domain-dependent DNA binding of Mad3 is not required, suggesting that Mad3 interacts with other DNA binding proteins to repress transcription. Interestingly, cerebellar tumors and pretumor cells derived from patched heterozygous mice express high levels of Mad3 compared with adjacent normal cerebellar tissue. Our studies support a novel role for Mad3 in cerebellar GNP proliferation and possibly tumorigenesis, and they challenge the current paradigm that Mad3 should antagonize Nmyc by competition for direct DNA binding via Max dimerization.
机译：在发育过程中，声波刺猬（Shh）一部分通过Nmyc的表达来调节小脑颗粒神经元前体（GNP）的增殖。我们目前的证据支持在Shh通路中调控Nmyc表达和GNP增殖的Mad家族成员Mad3的新型作用。 Mad3 mRNA在增殖过程中在GNP中短暂表达。培养的GNP以环巴胺依赖性方式响应Shh刺激表达Mad3。如通过溴脱氧尿苷掺入和Nmyc表达所测量，Mad3对于依赖Shh的GNP增殖是必需的。此外，在没有Shh的情况下，Mad3的过度表达足以诱导GNP增殖，而其他Mad蛋白则不足。结构功能分析表明，Mad3介导的GNP增殖需要最大二聚化和mSin3共表达的募集。出人意料的是，不需要Mad3的基本域依赖性DNA结合，这表明Mad3与其他DNA结合蛋白相互作用以抑制转录。有趣的是，与修补后的小脑组织相比，修补杂合子小鼠的小脑肿瘤和前肿瘤细胞表达高水平的Mad3。我们的研究支持Mad3在小脑GNP增殖和可能的肿瘤发生中的新作用，并且挑战了当前的范例，即Mad3应通过Max二聚化竞争直接DNA结合来拮抗Nmyc。

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