微RNA在大脑新皮层层次形成中的调控作用

The Regulatory Role of microRNA in Neocortical Layer Formation

种类多样的神经元有序排列和特异性的连接形成了大脑新皮层的6层组织,从而构成了神经系统高级功能的核心。了解大脑新皮层发育形成的机制将为理解哺乳动物乃至人类的生理与行为提供理论基础,也为神经系统疾病诊疗带来重大影响。本文以微RNA(microRNAs,miRNAs)为对象,结合笔者实验室工作,总结近年来所发现的miRNAs在大脑皮层层次形成过程中的研究进展,特别是在神经干细胞时序性命运决定、投射神经元多样性的形成、神经元放射状迁移,以及分裂后神经元进一步命运特化等方面的进展,为大脑皮层的发育机制研究提供新的思路。

Laminar organization is a hallmark of the mammalian neocortex,where the orderly arrangement of diverse neurons stereotypically forms into six distinct layers.The laminar structure provides a basis for the formation of precise neural circuits responsible for high-level cognitive functions.A deeper understanding of the mechanisms underlying neocortical layer formation and cell assembly in the brain will provide a more comprehensive insight into mammalian and even human physiology and behavior.It will also enable the development of novel diagnostic and therapeutic strategies for neurological disorders.To achieve this,it is imperative to elucidate the molecular regulatory networks that determine the fate of neurons in the neocortex.MicroRNAs(miRNAs)are small non-coding RNAs of 18-25 nucleotides in length that play important roles in the gene expression network.A large number of studies have reported that miRNAs are involved in various developmental processes within the nervous system.This review summarizes the progress of research on miRNAs that have been identified in recent years with regard to neocortical layer formation.We start with a comparative analysis of different Cre-line mediated conditional knockout mice for Dicer,a gene indispensable for the synthesis of almost all miRNAs.The results indicate that miRNAs are essential for the formation of neocortical layers,including the determination of the fate of projection neurons and the migration of these cells.Next,we summarize the regulatory roles of miRNAs in the coordinated execution of a series of developmental events that contribute to neocortical layer formation.First,the temporal patterning of neocortical neural progenitors is regulated by miRNAs.Two types of temporally opposite expression gradients and functionally antagonistic miRNAs modulate the competence of neural progenitors by changing their relative expression levels during neurogenesis,thereby shifting the progressive generation of neocortical neurons.Second,it is described that miRNAs influence lamination by regulating the fate of intermediate progenitor cells(IPCs).In particular,several miRNAs that are specifically expressed in multiple gyrencephalic species have been identified in recent years and are involved in regulating the generation of IPCs as well as the generation of upper layer neurons.Third,the regulatory roles of miRNAs in the migration of cortical projection neurons,including the multipolar to bipolar transition and other processes,were presented.Fourth,we described miRNAs that are expressed in postmitotic neurons but play roles in the further specification of different cortical projection neuron subtype identities,in particular the role of several miRNAs in the Mirg cluster in establishing different subtype identities of projection neurons in layer V,promoting corticospinal motor neuron(CSMN)identity but inhibiting callosal projection neuron(CPN)identity.Finally,we discussed current challenges in the study of miRNAs in neocortical layer formation and looked forward to future directions that deserve further exploration,such as the functions of a large number of newly discovered miRNAs,or whether miRNAs regulate the layer-dependent pattern of other neuronal cells with layer distribution features;the contribution of miRNAs in the rapid evolution of the neocortex,especially in the formation of characteristic structures in the primate neocortex;and the use of miRNAs as an entry point to explore finer regulatory networks.