The Hippo (MST1/2) pathway plays a critical role in restricting tissue growth in adults and modulating cell proliferation, differentiation, and migration in developing organs. Netrin1, a secreted laminin-related protein, is essential for nervous system development. However, the mechanisms underlying MST1 regulation by the extrinsic signals remain unclear. Here, we demonstrate that Netrin1 reduction in Parkinson’s disease (PD) activates MST1, which selectively binds and phosphorylates netrin receptor UNC5B on T428 residue, promoting its apoptotic activation and dopaminergic neuronal loss. Netrin1 deprivation stimulates MST1 activation and interaction with UNC5B, diminishing YAP levels and escalating cell deaths. Knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss, whereas blockade of MST1 phosphorylating UNC5B suppresses neuronal apoptosis. Remarkably, Netrin1 is reduced in PD patient brains, associated with MST1 activation and UNC5B T428 phosphorylation, which is accompanied by YAP reduction and apoptotic activation. Hence, Netrin1 regulates Hippo (MST1) pathway in dopaminergic neuronal loss in PD via UNC5B receptor.

Hippo（MST1 / 2）通路在限制成人组织生长和调节发育中器官的细胞增殖，分化和迁移中起着关键作用。Netrin1是一种与层粘连蛋白有关的分泌蛋白，对于神经系统发育至关重要。但是，由外部信号调节MST1的机制尚不清楚。在这里，我们证明Netrin1减少帕金森氏病（PD）激活MST1，它选择性地结合和磷酸化T428残基上的netrin受体UNC5B，促进其凋亡激活和多巴胺能神经元丢失。Netrin1剥夺刺激MST1激活并与UNC5B相互作用，从而降低YAP水平并加剧细胞死亡。UNC5B的敲除消除了netrin耗竭引起的多巴胺能丧失，而阻断MST1磷酸化UNC5B可抑制神经元凋亡。值得注意的是，PD病人大脑中的Netrin1减少，与MST1激活和UNC5B T428磷酸化有关，伴随着YAP减少和凋亡激活。因此，Netrin1通过UNC5B受体调节PD中多巴胺能神经元丢失的Hippo（MST1）途径。