Self-balanced regulation by the long non-coding RNALockdon the cell cycle progression of cortical neural progenitor cells through counteractingcisandtransroles

Abstract

AbstractNeural stem/progenitor cells (NSPCs) undergo active proliferation and exit the cell cycle upon precise regulation to produce differentiated progenies in order. Long non-coding RNAs (lncRNAs) have emerged as critical players in the developmental processes of NSPCs; however, relatively few have been shown to regulate the cell cyclein vivodirectly. Here, we identified an NSPC-expressed lncRNALockd(lncRNA downstream ofCdkn1b) in the developing forebrain. Usingin vivoloss of function models by premature termination ofLockdtranscription via knockin polyadenylation signals or shRNA-mediated knockdown ofLockd(Lockd-KD), we show thatLockdis required for proper cell cycle progression of cortical NSPCs and the production of TBR2+intermediate neural progenitor cells during cortical development. Interestingly, a comparison of genetic profiling in the two models reveals thatLockdpromotes the expression of two counteracting cell cycle-related genes,Cdkn1b in cisandCcnd1 in trans. Overexpression ofCcnd1orCdkn1b-KD can rescue the cellular phenotypes of reduced cycling progenitors inLockd-KD. Our results imply that lncRNA could act through distinctcisandtransmechanisms to achieve a self-balanced function.