Abstract：
Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.
摘要：
家族性自主神经障碍(FD)是由基因ELP1中的剪接位点突变引起的常染色体隐性遗传疾病,其不成比例地影响神经元。虽然经典的特征是感觉和自主神经元的缺陷，中枢神经系统的神经元缺陷也已被描述。虽然,ELP1在正常发育和成年小脑中的表达仍然很高，它在小脑发育中的作用是未知的。探讨Elp1在小脑中的作用,我们敲除了小脑颗粒细胞祖细胞（GCP）中的Elp1，并检查了动物行为和细胞组成的结果。我们发现Elp1（Elp1cKO）的GCP特异性条件性敲除导致8周龄的共济失调。细胞鉴定表明，动物的小脑较小，颗粒细胞较少。这种缺陷早在出生后7天就已经很明显了，当Elp1cKO动物的有丝分裂GCP和Purkinje树突较短时。通过分子表征,我们发现Elp1的缺失与GCP中凋亡细胞死亡和细胞应激途径的增加有关.我们的研究证明了ELP1在发育中的小脑中的重要性，这表明GC谱系中Elp1的缺失也可能在FD患者的进行性共济失调表型中发挥作用。
