TSUKUSHI associate idiopathic normal pressure hydrocephalus with neurodevelopmental disorder in mice

Idiopathic normal pressure hydrocephalus (iNPH), often observed by cranial enlargement and ventricular expansion, is developed with vomiting, gait disturbance, lack of concentration (Hebb and Cusimano, 2001). Abnormality of neural stem cell (NSC) niche in the LV is known as the reason of iNPH, however the relationship with iNPH is not fully understood (Carter et al., 2012; Ferland et al., 2009; Kahle et al., 2016). We show that Wnt antagonist TSUKUSHI (TSK) deficiency results in neonatal hydrocephalus with neurodevelopmental disorder-like symptoms by altering cell proliferation and differentiation of the NSC niche in mice. We found multiple TSK variants in the genome of hydrocephalus patients and reproduced multiple variant of TSK lost binding activity for the receptor Frizzled-3 and cause hydrocephalus in mice. In addition, transcriptome revealed loss of TSK disturbed profile of Wnt signaling, tight junction and development of ventricular cilia. Finally, we showed TSK protein or Wnt antagonist C59 injection to TSK-KO mice suppress lateral ventricle expansion. These results indicate that TSK modulate lateral ventricle development and TSK is therapeutics candidate for iNPH.

特发性正常压力脑积水（idiopathic normal pressure hydrocephalus, iNPH）常表现为颅骨增大与脑室扩张，患者可伴随呕吐、步态障碍及注意力下降（Hebb与Cusimano，2001）。侧脑室（lateral ventricle, LV）内的神经干细胞（neural stem cell, NSC）微环境异常被认为是iNPH的潜在致病机制，但其与iNPH的具体关联尚未完全阐明（Carter等，2012；Ferland等，2009；Kahle等，2016）。本研究证实，Wnt拮抗剂TSUKUSHI（TSK）的缺失可通过改变小鼠神经干细胞微环境的细胞增殖与分化状态，诱发伴随神经发育障碍样症状的新生儿脑积水。我们在脑积水患者的基因组中发现了多种TSK变异体，并验证到部分TSK变异体丧失了与受体Frizzled-3的结合能力，且可在小鼠体内诱发脑积水。此外，转录组（transcriptome）测序分析显示，TSK的缺失会扰乱Wnt信号通路、紧密连接及脑室纤毛发育的相关基因表达谱。最后，我们发现向TSK基因敲除（TSK-KO）小鼠注射TSK蛋白或Wnt拮抗剂C59，可有效抑制侧脑室扩张。上述结果表明，TSK可调控侧脑室发育，且TSK有望成为iNPH的潜在治疗候选靶点。