Wang Yanyan, Kraemer Nadine, Schneider Joanna, Ninnemann Olaf, Weng Kai, Hildebrand Michael, Reid Joshua, Li Na, Hu Hao, Mani Shyamala, Kaindl Angela M
Institute of Cell Biology and Neurobiology, Charite - Universitatsmedizin Berlin, Berlin, Germany; Department of Pediatric Neurology, Charité - Universitatsmedizin Berlin, Berlin, Germany.
Department of Pediatric Neurology, Charité - Universitatsmedizin Berlin, Berlin, Germany; Center for Chronically Sick Children, Charité - Universitatsmedizin Berlin, Berlin, Germany.
HGG Adv. 2025 Jan 9;6(1):100363. doi: 10.1016/j.xhgg.2024.100363. Epub 2024 Oct 9.
Neural tube closure defect pathomechanisms in human embryonic development are poorly understood. Here we identified spina bifida patients expressing novel variants of the TOGARAM gene family. TOGARAM1 has been associated with the ciliopathy Joubert syndrome, but its connection to spina bifida and role in neural development is unknown. We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects. Neural stem cells from Togaram1 knockout embryos showed reduced cilia and defects in Shh signaling. Overexpression in IMCD3 and HEK293 cells of TOGARAM1 carrying the variant found in the spina bifida patient resulted in cilia defect along with reduced pericentriolar material one (PCM1), a critical constituent of centriolar satellites involved in transporting proteins toward the centrosome and primary cilia. Our results demonstrate the role of TOGARAM1 in regulating Shh signaling during early neural development that is critical for neural tube closure and elucidates potential mechanisms whereby the ciliopathy-associated gene TOGARAM1 gives rise to spina bifida aperta in humans.
人类胚胎发育过程中神经管闭合缺陷的发病机制尚不清楚。在此，我们鉴定出表达TOGARAM基因家族新变体的脊柱裂患者。TOGARAM1与纤毛病乔伯综合征有关，但其与脊柱裂的联系以及在神经发育中的作用尚不清楚。我们发现Togaram1在神经管中表达，Togaram1基因敲除小鼠有异常纤毛、音猬因子（Shh）信号传导减少、神经管模式异常，并表现出神经管闭合缺陷。来自Togaram1基因敲除胚胎的神经干细胞显示纤毛减少和Shh信号传导缺陷。在IMCD3和HEK293细胞中过表达在脊柱裂患者中发现的携带该变体的TOGARAM1，导致纤毛缺陷以及中心粒旁物质1（PCM1）减少，PCM1是中心粒卫星的关键组成部分，参与将蛋白质运输到中心体和初级纤毛。我们的结果证明了TOGARAM1在早期神经发育过程中调节Shh信号传导的作用，这对神经管闭合至关重要，并阐明了与纤毛病相关的基因TOGARAM1在人类中导致开放性脊柱裂的潜在机制。
