PRDM16 cooperates with LHX2 to shape the human brain
In the developing mouse brain, PRDM16 exhibits robust expression in radial glia (RG) progenitors, serving as one of the conserved core RG genes shared between humans and mice. Much is known regarding the functions of PRDM16 in the developing mouse brain, yet its roles in the developing human brain are less explored. Our study was motivated by detecting a patient with a de novo nonsense mutation in PRDM16 exhibiting lissencephaly and microcephaly features. We introduced the mutation in human stem cells in both homozygous and heterozygous manner and generated human cortical organoids. The organoids differed in cell cycle parameters, and RNA-seq demonstrated changes in cell adhesion and WNT-signaling, which were confirmed by immunostaining. We further generated ChIP-seq data from human fetuses and compared the results to ChIP-seq data previously obtained from mice and differentially expressed genes in humans and mice (REFS he and baizabal papers). The top detected motif matched LHX2, so we compared our data with recently acquired LHX2 ChIP-seq data from the mouse. Our studies show highly conserved genes and pathways suggesting that PRDM16 and LHX2 complex and collaborate in the developing mouse and human brains. The multifaceted nature of PRDM16 and its intricate involvement in transcriptional regulation and various developmental processes highlight its importance in understanding neurodevelopmental mechanisms. Overall design: Samples are forebrain organoids from day 32, from WIBR3 control line and PRDM16-KO line. 3 biological replecates were used