Department of Biological Sciences, Clemson University, Clemson, SC, USA
Vijay Shankar
Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA; Center for Human Genetics, Clemson University, Greenwood, SC, USA
Jennie C. Holmberg
Department of Biological Sciences, Clemson University, Clemson, SC, USA
Aidan M. Sokolov
Department of Biological Sciences, Clemson University, Clemson, SC, USA
Victoria N. Neckles
Department of Biological Sciences, Clemson University, Clemson, SC, USA
Kaitlyn Williams
Clemson University Genomics and Bioinformatics Facility (CUGBF), Clemson University, Clemson, SC, USA
Rachel Lyman
Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA; Center for Human Genetics, Clemson University, Greenwood, SC, USA
Trudy F.C. Mackay
Department of Biochemistry and Genetics, Clemson University, Clemson, SC, USA; Center for Human Genetics, Clemson University, Greenwood, SC, USA
David M. Feliciano
Department of Biological Sciences, Clemson University, Clemson, SC, USA; Center for Human Genetics, Clemson University, Greenwood, SC, USA; Corresponding author
Summary: 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.
