Microcephaly-associated WDR62 mutations hamper Golgi apparatus-to-spindle pole shuttling in human neural progenitors

Abstract

WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions during corticogenesis. Recessive mutations in WDR62 are associated with structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated a C-terminal truncating mutation (D955AfsX112) in WDR62 using induced pluripotent stem cells (iPSCs) obtained from a patient with MCPH2. We generated neuroepithelial stem (NES) cells and cerebro-cortical progenitors and neurons from patient-derived and isogenic retro-mutated iPSC lines. We found that WDR62 dysfunction resulted in impaired cell cycle progression and alterations of the neurogenic trajectories of iPSC neuroderivatives. Moreover, we report WDR62 localization at the Golgi apparatus during interphase, both in human neural progenitors in vitro and in human fetal brain tissue. WDR62 shuttling from the Golgi apparatus to spindle poles is dynamic and microtubule-dependent. Impairment of WDR62 function and localization results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in MCPH etiology.

Generation and benchmarking of a collection of hiPSC lines from Schizophrenia Patients with Diverse Clinical Profiles

“…Human induced pluripotent stem cells (hiPSCs) provide a promising alternative, allowing the creation of SCZ patient-specific disease models to explore cellular and molecular phenotypes (Angulo Salavarria et al, 2023). Indeed, hiPSCs enable the generation of various brain-specific cell types, including cortical neurons, interneurons, astrocytes, and microglia (Abud et al, 2017; Muffat et al, 2016; Dell’Amico et al 2023). Several studies identified impaired neuronal maturation, reduction of neurite length and outgrowth through these cellular populations, along with an excitatory-inhibitory imbalance, including enhanced GABAergic-related neuronal expression and genetic upregulation (Brennand et al, 2011; Park et al, 2020; Sawada et al, 2020).…”