Tsc2 coordinates neuroprogenitor differentiation

Victoria A Riley; Vijay Shankar; Jennie C Holmberg; Aidan M Sokolov; Victoria N Neckles; Kaitlyn Williams; Rachel Lyman; Trudy F C Mackay; David M Feliciano

doi:10.1016/j.isci.2023.108442

Tsc2 coordinates neuroprogenitor differentiation

iScience. 2023 Nov 14;26(12):108442. doi: 10.1016/j.isci.2023.108442. eCollection 2023 Dec 15.

Authors

Victoria A Riley¹, Vijay Shankar^{2

3}, Jennie C Holmberg¹, Aidan M Sokolov¹, Victoria N Neckles¹, Kaitlyn Williams⁴, Rachel Lyman^{2

3}, Trudy F C Mackay^{2

3}, David M Feliciano^{1

3}

Affiliations

¹ Department of Biological Sciences, Clemson University, Clemson, SC, USA.
² Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA.
³ Center for Human Genetics, Clemson University, Greenwood, SC, USA.
⁴ Clemson University Genomics and Bioinformatics Facility (CUGBF), Clemson University, Clemson, SC, USA.

Abstract

Neural stem cells (NSCs) of the ventricular-subventricular zone (V-SVZ) generate numerous cell types. The uncoupling of mRNA transcript availability and translation occurs during the progression from stem to differentiated states. The mTORC1 kinase pathway acutely controls proteins that regulate mRNA translation. Inhibiting mTORC1 during differentiation is hypothesized to be critical for brain development since somatic mutations of mTORC1 regulators perturb brain architecture. Inactivating mutations of TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC). TSC patients have growths near the striatum and ventricles. Here, it is demonstrated that V-SVZ NSC Tsc2 inactivation causes striatal hamartomas. Tsc2 removal altered translation factors, translatomes, and translational efficiency. Single nuclei RNA sequencing following in vivo loss of Tsc2 revealed changes in NSC activation states. The inability to decouple mRNA transcript availability and translation delayed differentiation leading to the retention of immature phenotypes in hamartomas. Taken together, Tsc2 is required for translational repression and differentiation.

Keywords: Cell biology; Molecular biology; Molecular mechanism of gene regulation; Neuroscience; Stem cells research; Transcriptomics.

Abstract

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