Identification of a Mitogen for Neuronal Progenitors in the Embryonic Cerebellum

描述（由申请人提供）：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。虽然已经详细研究了颗粒神经元的发育，但控制其生长和分化的信号仍然不清楚。在出生后的发育过程中，颗粒神经元前体（GNP）的增殖是由邻近的浦肯野细胞产生的有丝分裂原Sonic hedgehog（Shh）驱动的。有趣的是，GNP在胚胎发育期间也增殖，在Shh分泌之前的阶段;负责这种增殖的有丝分裂原是未知的。我们的初步研究表明，有丝分裂活性存在于胚胎小脑提取物。在这里，我们建议确定这种丝裂原，并研究其在小脑发育中的作用。具体而言，我们的目标是（1）使用组织显微切割和细胞分选来确定有丝分裂原的来源，（2）使用表达克隆来在分子水平上鉴定有丝分裂原。这些研究不仅将提供对控制小脑发育的机制的深入了解，而且还将确定可能在髓母细胞瘤形成中重要的新信号通路。 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（包括共济失调和自闭症）具有重要意义。此外，由于控制生长和分化的信号在癌症中经常失调，这些研究可能会揭示小脑肿瘤如髓母细胞瘤的病因。

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.