The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool
Adelaida Kolaj,
Siraj K. Zahr,
Beatrix S. Wang,
Taylor Krawec,
Hilal Kazan,
Guang Yang,
David R. Kaplan,
Freda D. Miller
Affiliations
Adelaida Kolaj
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada
Siraj K. Zahr
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada
Beatrix S. Wang
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Taylor Krawec
Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
Hilal Kazan
Department of Computer Engineering, Antalya Bilim University, Antalya, Turkey
Guang Yang
Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada; Department of Biochemistry and Cell Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada; Owerko Centre, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
David R. Kaplan
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
Freda D. Miller
Program in Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; Corresponding author
Summary: Here, we ask how developing precursors maintain the balance between cell genesis for tissue growth and establishment of adult stem cell pools, focusing on postnatal forebrain neural precursor cells (NPCs). We show that these NPCs are transcriptionally primed to differentiate and that the primed mRNAs are associated with the translational repressor 4E-T. 4E-T also broadly associates with other NPC mRNAs encoding transcriptional regulators, and these are preferentially depleted from ribosomes, consistent with repression. By contrast, a second translational regulator, Cpeb4, associates with diverse target mRNAs that are largely ribosome associated. The 4E-T-dependent mRNA association is functionally important because 4E-T knockdown or conditional knockout derepresses proneurogenic mRNA translation and perturbs maintenance versus differentiation of early postnatal NPCs in culture and in vivo. Thus, early postnatal NPCs are primed to differentiate, and 4E-T regulates the balance between cell genesis and stem cell expansion by sequestering and repressing mRNAs encoding transcriptional regulators.
