ABSTRACT
The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Cerebral Cortex , Down Syndrome/genetics , Down Syndrome/pathology , Gene Expression Regulation, Developmental/genetics , Nerve Tissue Proteins/genetics , Neurogenesis/genetics , Age Factors , Animals , Animals, Newborn , Calbindins/metabolism , Carrier Proteins/metabolism , Cell Cycle Proteins/metabolism , Cell Death/genetics , Cerebral Cortex/embryology , Cerebral Cortex/growth & development , Cerebral Cortex/pathology , DNA-Binding Proteins/metabolism , Disease Models, Animal , Embryo, Mammalian , Homeodomain Proteins/metabolism , Interneurons/metabolism , Interneurons/pathology , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Nuclear Proteins/metabolism , Oligodendrocyte Transcription Factor 2 , POU Domain Factors/metabolism , Parvalbumins/metabolism , Repressor Proteins/metabolism , Transcription Factors/metabolism , Trinucleotide Repeats/geneticsABSTRACT
Multiple sclerosis (MS), a demyelinating disorder of the central nervous system (CNS), remains among the most prominent and devastating diseases in contemporary neurology. Despite remarkable advances in anti-inflammatory therapies, the inefficiency or failure of myelin-forming oligodendrocytes to remyelinate axons and preserve axonal integrity remains a major impediment for the repair of MS lesions. To this end, the enhancement of remyelination through endogenous and exogenous repair mechanisms and the prevention of axonal degeneration are critical objectives for myelin repair therapies. Thus, recent advances in uncovering myelinating cell sources and the intrinsic and extrinsic factors that govern neural progenitor differentiation and myelination may pave a way to novel strategies for myelin regeneration. The scope of this review is to discuss the potential sources of stem/progenitor cells for CNS remyelination and the molecular mechanisms underlying oligodendrocyte myelination.