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

doi:10.1016/j.celrep.2023.112242

The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool

Cell Rep. 2023 Mar 28;42(3):112242. doi: 10.1016/j.celrep.2023.112242. Epub 2023 Mar 15.

Authors

Adelaida Kolaj¹, Siraj K Zahr², Beatrix S Wang³, Taylor Krawec⁴, Hilal Kazan⁵, Guang Yang⁶, David R Kaplan⁷, Freda D Miller⁸

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
⁵ Department of Computer Engineering, Antalya Bilim University, Antalya, Turkey.
⁶ 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.
⁷ 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.
⁸ 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. Electronic address: freda.miller@msl.ubc.ca.

PMID: 36924490
DOI: 10.1016/j.celrep.2023.112242

Abstract

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.

Keywords: 4E-T; CP: Neuroscience; CP: Stem cell research; Cpeb4; brain development; neural stem cell; neurogenesis; translational repression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / physiology
Neural Stem Cells* / metabolism
Neurons / metabolism
Nucleocytoplasmic Transport Proteins / metabolism
Processing Bodies
Protein Biosynthesis
RNA, Messenger / genetics
RNA, Messenger / metabolism
Repressor Proteins / metabolism

Substances

Repressor Proteins
RNA, Messenger
Nucleocytoplasmic Transport Proteins