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Protein Phosphatase 4 and Smek complex negatively regulate Par3 and promote neuronal differentiation of neural stem/ progenitor cells Jungmook Lyu1,2, Hee-Ryang Kim1, Vicky Yamamoto2, Si Ho Choi2, Zong Wei2, Choun-Ki Joo1, and Wange Lu2 1Catholic Institute for Visual Science, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Korea 2The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Los Angeles, California 90042, USA SUMMARY Neural progenitor cells (NPCs) are multipotent cells that can self-renew and differentiate into neurons and glial cells. However, mechanisms that control their fate decisions are poorly understood. Here, we show that Smek1, a regulatory subunit of the serine/threonine protein phosphatase PP4, promotes neuronal differentiation and suppresses proliferative capacity of NPCs. We identify the cell polarity protein Par3, a negative regulator of neuronal differentiation, as a novel Smek1 substrate and demonstrate that Smek1 suppresses its activity. We also show that Smek1, which is predominantly nuclear in NPCs, is excluded from nucleus during mitosis, allowing it to interact with cortical/cytoplasmic Par3 and mediate its dephosphorylation by the catalytic subunit PP4c. These results identify the PP4/Smek1 complex as a key regulator of neurogenesis. INTRODUCTION Neural stem and progenitor cells located in the ventricular zone (VZ) of the embryonic neocortex are mitotically active, self-renewing cells with the potential to produce differentiated cell types (Temple, 2001). During cortical development, postmitotic neurons generated from NPCs migrate radially out of the VZ and form the cortical plate (CP) in an “inside-out pattern,” eventually establishing a six-layered cortex (Kriegstein et al., 2006). The timing of neuronal differentiation determines the siz