Human Gene FOXM1 Regulates The Formation Of Cortical Folding

The brain is the center of the mammalian organism,which plays a key role in animal physiological activities,the body’s response and cognition.The cerebral cortex is a highly complex and delicately ordered structure specialized in the mammalian brain.Different cell types in the brain coordinate together,which interact to form a massively structured neural network.During the development and evolution of mammalian brain,neocortex expansion and folding are closely related to human intelligence and serve as the neural basis for higher functions.In order to adapt to the limitation of skull volume,the human cerebral cortex with a larger surface area has a relatively complex folding of cerebral cortex.However,abnormal expansion or misfolding of the developmental cortex leads to developmental diseases and brain malformations.So,it is very important to explore the mechanisms that influence cortical expansion and folding formation.During brain development,outer subventricular zone(OSVZ)plays a key role in the cortical development of gyrencephalic species,such as humans and ferrets compared to lissencephalic species such as rodents.This region is located laterally,near the meninges,and contains an abundance of basal radial glia(bRG)and intermediate progenitors(IP)cells that undergo multiple rounds of symmetric and asymmetric division.The cellular and molecular mechanisms regulating the development of OSVZ and bRG have not been fully studied.Studies have shown that an increase in the proliferative potential of neural progenitor cells underlies the expansion of the cortex and its convoluted appearance.FOXM1 is a typical proliferation-related transcription factor and a key cell cycle regulator.Human FOXM1 is alternatively spliced.Alternative splicing creates a new chimeric protein that provides an evolutionary advantage.However,the function of human FOXM1 in brain development remains unknown.Published databases showed that the human FOXM1 gene expressed in RGCs and IPCs.In addition,we found that FOXM1 is mainly expressed in the ventricular zone(VZ),inner subventricular zone(iSVZ)and OSVZ regions of the brain in cortical tissue sections.These results suggest that FOXM1 may play an important role in brain development.To identify the functions of FOXM1 in embryonic neurogenesis,we overexpressed the human FOXM1 gene in the cortex of E13.5 embryonic mice by in utero electroporation,and found an increased number of neural progenitor cells,especially the basal precursor cells.The expression of human FOXM1 promoted the proliferation of neural progenitors,a decrease in cell cycle exits and an increase in the number of neurons,resulting in cortical expansion and folding in mice brain.We found that human-specific protein sequences further promoted the generation of basal progenitor cells.RNA-seq analysis revealed that Lin28a gene,a well-known RNA-binding protein were significantly up-regulated in hFOXM1-cKI mice cortices.And CHIP analysis showed that the human FOXM1 gene increases neural progenitor cell proliferation by binding to the lin28a promoter.Furthermore,overexpression of LIN28A rescues the proliferation of human FOXM1 knockout neural progenitor cells.Taken together,our results reveal an important function of FOXM1 in the developing cortex,thus providing new insights into the molecular mechanisms of FOXM1 expansion and folding in the cerebral cortex.Our study shows that human FOXM1 is an important regulator of brain development,suggesting that a single human gene can alter changes in brain development that contribute to brain evolution.