Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Developmental Origins of Pediatric Cancer Junior Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, A partnership between DKFZ and Heidelberg University Hospital, Germany.
Neurobiol Dis. 2024 Sep;199:106600. doi: 10.1016/j.nbd.2024.106600. Epub 2024 Jul 10.
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 (Elp1) 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 Elp1 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.
家族性自主神经异常症（FD）是一种常染色体隐性疾病，由 ELP1 基因的剪接位点突变引起，该突变会不成比例地影响神经元。尽管 FD 经典特征为感觉神经元和自主神经元缺陷，但中枢神经系统的神经元缺陷也已有描述。虽然 ELP1 在正常发育和成年小脑中的表达仍然很高，但它在小脑发育中的作用尚不清楚。为了研究 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，并观察其对动物行为和细胞组成的影响。我们发现，GCP 特异性条件性敲除 Elp1（Elp1）会导致 8 周龄时出现共济失调。细胞特征分析表明，动物的小脑更小，颗粒细胞更少。这种缺陷早在出生后 7 天就很明显，此时 Elp1 动物的有丝分裂 GCP 也更少，浦肯野细胞树突更短。通过分子特征分析，我们发现 Elp1 的缺失与 GCP 中细胞凋亡和细胞应激途径的增加有关。我们的研究表明 ELP1 在发育中的小脑中的重要性，并表明 GC 谱系中 Elp1 的缺失也可能在 FD 患者进行性共济失调表型中发挥作用。
