Tmem216 deficiency induces hydrocephalus via impaired ciliogenesis and disrupted ependymal planar polarity in mice

• 成果类型: Article
• 署名作者: Gong, Qianqian; Lv, Zhuowen; Dou, Zhilin; Wang, Sen; Zhang, Keyi; Guo, Yuyu; Wang, Yingying; Shao, Ming; Su, Ling; Liu, Xiangguo; Sun, Xiaoyang
• 署名单位: Shandong University; Shandong University; Shandong University; Shandong University; Shandong University; Shandong University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2615477123
• 发表日期: 2026-09-15
• 页码: e2615477123
• 关键词: hydrocephalus; ependymal cell; Tmem216; cilia; planar cell polarity; PERTURB CILIOGENESIS; cell polarity; PRIMARY CILIA; CAUSE JOUBERT; MECKEL; brain; proliferation; mutations; reveals; genes

摘要

Defects in multiciliated ependymal cells (ECs), which line the cerebral ventricular walls and generate unidirectional cerebrospinal fluid (CSF) flow through coordinated ciliary beating, can lead to CSF accumulation and hydrocephalus. TMEM216, a ciliopathy-associated gene mutated in Joubert, Meckel, and related syndromes, encodes an essential component of the protein complexes that form the transition zone (TZ) at the base of primary cilia. Here, we demonstrate that central nervous system-specific inactivation of Tmem216 results in severe postnatal hydrocephalus. TMEM216 localizes to the TZ of motile cilia in ECs and the TZ of primary cilia in radial glia cells (RGCs), the embryonic precursors of ECs. While Tmem216-deficient ECs differentiate normally, TZ structure and ciliogenesis in both ECs and RGCs are severely disrupted, as shown by reduced cilia abundance and disrupted ciliary ultrastructure. These defective cilia exhibit immobility or dyskinetic movement, resulting in significantly slower CSF flow in Tmem216 mutants than controls. In addition to aberrant ciliogenesis and ciliary dysfunction, Tmem216 ablation disrupts both translational polarity (asymmetric positioning of cilia on the apical area) in RGCs and ECs, as well as rotational polarity (unidirectional orientation of basal bodies within individual ECs and intercellular rotational alignment of motile cilia) in ECs. These findings identify TMEM216 as a critical TZ protein essential for ciliogenesis during ependymal development and establishing ependymal planar cell polarity.