A Translational Repression Complex in Developing Mammalian Neural Stem Cells that Regulates Neuronal Specification

• Published in: Neuron (Cambridge, Mass.) Vol. 97; no. 3; pp. 520 - 537.e6
• Main Authors: Zahr, Siraj K., Yang, Guang, Kazan, Hilal, Borrett, Michael J., Yuzwa, Scott A., Voronova, Anastassia, Kaplan, David R., Miller, Freda D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2018; Elsevier Limited
• Subjects: 4E-T; Animals; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; cortex; development; Embryos; Ependymoglial Cells - metabolism; Eukaryotic Initiation Factor-4E - metabolism; Female; Gene Expression Regulation, Developmental; Glial stem cells; Male; Mice; Nerve Tissue Proteins - metabolism; Neural stem cells; Neural Stem Cells - metabolism; Neurogenesis; neuronal subtype specification; Neurons; POU Domain Factors - metabolism; Primary Cell Culture; Proteins; Pumilio; radial precursors; Repressor Proteins - metabolism; RNA, Messenger - metabolism; RNA-binding protein; RNA-Binding Proteins - metabolism; Sequence Analysis, RNA; Stem cell transplantation; Stem cells; Temporal cortex; Transcription; translational repression; cortex; 4E-T; development; RNA-binding protein; neural stem cells; neurogenesis; radial precursors; neuronal subtype specification; translational repression; Pumilio
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2017.12.045

The mechanisms instructing genesis of neuronal subtypes from mammalian neural precursors are not well understood. To address this issue, we have characterized the transcriptional landscape of radial glial precursors (RPs) in the embryonic murine cortex. We show that individual RPs express mRNA, but not protein, for transcriptional specifiers of both deep and superficial layer cortical neurons. Some of these mRNAs, including the superficial versus deep layer neuron transcriptional regulators Brn1 and Tle4, are translationally repressed by their association with the RNA-binding protein Pumilio2 (Pum2) and the 4E-T protein. Disruption of these repressive complexes in RPs mid-neurogenesis by knocking down 4E-T or Pum2 causes aberrant co-expression of deep layer neuron specification proteins in newborn superficial layer neurons. Thus, cortical RPs are transcriptionally primed to generate diverse types of neurons, and a Pum2/4E-T complex represses translation of some of these neuronal identity mRNAs to ensure appropriate temporal specification of daughter neurons. •Radial precursors are transcriptionally primed to make diverse neuronal subtypes•The 4E-T repressor forms a complex with Pum2 during neurogenesis•Neuronal specification mRNAs are translationally repressed in radial precursors•Disruption of the Pum2/4E-T complex causes misspecification of cortical neurons Zahr et al. show that cortical RPs are transcriptionally primed to generate diverse neuronal subtypes and that translational repression mechanisms determine which transcription factor mRNAs are translated to ensure appropriate temporal specification of daughter neurons.