Identification of a Mitogen for Neuronal Progenitors in the Embryonic Cerebellum

描述(申请人提供)：小脑对运动协调和认知功能至关重要。颗粒神经元是小脑回路的关键组成部分，被认为是儿童脑肿瘤髓母细胞瘤的起源细胞。虽然颗粒神经元的发育已经得到了详细的研究，但控制其生长和分化的信号仍不清楚。在出生后的发育过程中，颗粒神经元前体(GNPs)的增殖是由邻近浦肯野细胞产生的有丝分裂原Sonic Hedgehog(Shh)驱动的。有趣的是，GNPs也在胚胎发育期间增殖，在Shh分泌之前的一个阶段；负责这种增殖的有丝分裂原尚不清楚。我们的初步研究表明，胚胎小脑的提取物中存在有丝分裂活性。在这里，我们建议鉴定这种有丝分裂原，并研究它在小脑发育中的作用。具体地说，我们的目标是(1)使用组织显微解剖和细胞分选来确定丝裂原的来源，以及(2)使用表达克隆来在分子水平上鉴定丝裂原。这些研究不仅将提供对控制小脑发育的机制的洞察，还将识别可能在髓母细胞瘤形成中重要的新的信号通路。 公共卫生相关性：识别控制小脑神经元产生的信号可能对理解小脑结构和功能受损的疾病有重要意义，包括共济失调和自闭症。此外，由于控制生长和分化的信号在癌症中通常是失调的，这些研究可能有助于揭示髓母细胞瘤等小脑肿瘤的病因。

DESCRIPTION (provided by applicant): The cerebellum is critical for motor coordination and cognitive function. Granule neurons are a key component of cerebellar circuitry and are thought to represent the cell of origin for the pediatric brain tumor medulloblastoma. While the development of granule neurons has been studied in detail, the signals that control their growth and differentiation remain unclear. During postnatal development, proliferation of granule neuron precursors (GNPs) is driven by the mitogen Sonic hedgehog (Shh), which is produced from neighboring Purkinje cells. Interestingly, GNPs also proliferate during embryonic development, at a stage prior to Shh secretion; the mitogen responsible for this proliferation is unknown. Our preliminary studies indicate that a mitogenic activity is present in extracts from the embryonic cerebellum. Here we propose to identify this mitogen and study its role in cerebellar development. Specifically, we aim to (1) Use tissue microdissection and cell sorting to determine the source of the mitogen, and (2) Use expression cloning to identify the mitogen at a molecular level. These studies will not only provide insight into the mechanisms that control cerebellar development, but will also identify novel signaling pathways that may be important in medulloblastoma formation. PUBLIC HEALTH RELEVANCE: Identifying the signals that control production of neurons in the cerebellum may have important implications for understanding diseases in which cerebellar structure and function are impaired, including ataxia and autism. In addition, since signals that control growth and differentiation are often dysregulated in cancer, these studies may shed light on the etiology of cerebellar tumors such as medulloblastoma.