Biomedical subjects
Publications and source records attributed to Mark F Mehler.
Increasing evidence suggests that the development and function of the nervous system is heavily dependent on RNA editing and the intricate spatiotemporal expression of a wide repertoire of non-coding RNAs, including micro RNAs, small nucleolar RNAs and longer non-coding RNAs. Non-coding RNAs may provide the key to understanding the multi-tiered links between neural development, nervous system function, and neurological diseases.
Recent studies suggest that specific neural basic helix-loop-helix (HLH; i.e., Olig1 and Olig2, Mash1), associated inhibitory HLH (i.e., Id2 and Id4), high-mobility group domain (i.e., Sox10), and homeodomain (i.e., Nkx2.2) transcription factors are involved in oligodendrocyte (OL) lineage specification and progressive stages of maturation including myelination. However, the developmental interplay among these lineage-selective determinants, in a cell- and maturational stage-specific context, has not yet been defined. We show here in vivo and in vitro developmental expression profiles for these distinct classes of transcriptional regulators of OLs. We show that progressive stages of OL lineage maturation are characterized by dynamic changes in the subcellular distribution of these transcription factors and by different permutations of combinatorial transcriptional codes. Transient transfections of these precise combinatorial codes with a luciferase reporter gene driven by the myelin basic protein promoter define how changes in the molecular composition of these transcriptional complexes modulate myelin gene expression. Our overall findings suggest that the dynamic interplay between developmental stage-specific classes of transcriptional activators and associated inhibitory factors orchestrate myelin gene expression during terminal maturation of the mammalian CNS.
Recent studies documenting the phenomenon of de novo neurogenesis within the adult brain have propelled this area of research to the forefront of neuroscience investigations and stroke pathogenesis and treatment. Traditional theories have suggested that the central nervous system is incapable of neural regeneration; hence the emergence of the field of stem cell biology as a discipline devoted to uncovering novel forms of neural repair. However, several recent experimental observations have shown that the adult brain is capable of ongoing neurogenesis in discrete regions of the uninjured brain and additional forms of endogenous neural regeneration in the presence of an inciting event (induction neurogenesis). Induction neurogenesis has the potential for providing new insights into the cause and treatment of acute stroke syndromes.
Bone morphogenetic proteins (BMPs) promote astrocytic differentiation of cultured subventricular zone stem cells. To determine whether BMPs regulate the astrocytic lineage in vivo, transgenic mice were constructed that overexpress BMP4 under control of the neuron-specific enolase (NSE) promoter. Overexpression of BMP4 was first detectable by Western analysis on embryonic day 16 and persisted into the adult. The overexpression of BMP4 resulted in a remarkable 40% increase in the density of astrocytes in multiple brain regions accompanied by a decrease in the density of oligodendrocytes ranging between 11 and 26%, depending on the brain region and the developmental stage. No changes in neuron numbers or the pattern of myelination were detected, and there were no gross structural abnormalities. Similar phenotypes were observed in three independently derived transgenic lines. Coculture of transgenic neurons with neural progenitor cells significantly enhanced astrocytic lineage commitment by the progenitors; this effect was blocked by the BMP inhibitor Noggin, indicating that the stimulation of astrogliogenesis was due to BMP4 release by the transgenic neurons. These observations suggest that BMP4 directs progenitor cells in vivo to commit to the astrocytic rather than the oligodendroglial lineage. Further, differentiation of radial glial cells into astrocytes was accelerated, suggesting that radial glia were a source of at least some of the supernumerary astrocytes. Therefore, BMPs are likely important mediators of astrocyte development in vivo.
During cerebral cortical development, excitatory glutamatergic projection neurons are generated from neural stem cells intrinsic to the early embryonic cortical ventricular zone by a process of radial migration, whereas most inhibitory gamma-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes (OLs) appear to be elaborated from ventral forebrain stem cells that initially undergo tangential cortical migration before terminal lineage maturation. In contrast to the more compartmentalized developmental organization of the spinal cord, the generation of neurons and OLs from a common ventral forebrain stem cell would expose these cells to the sequential actions of ventral and dorsal gradient morphogens [sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs)] that normally mediate opposing developmental programs. Here we report that Shh promotes GABAergic neuronalOL lineage restriction of forebrain stem cells, in part, by activation of the basic helix-loop-helix transcription factors, Olig2 and Mash1. In mutant mice with a generalized defect in tangential cortical migration (Dlx12--), there is a profound and selective reduction in the elaboration of both cortical GABAergic neurons and OLs. Our studies further demonstrate that the sequential elaboration of cortical GABAergic neurons and OLs from common Shh-responsive ventral forebrain progenitors requires the spatial and temporal modulation of cortical BMP signaling by BMP ligands and the BMP antagonist, noggin, respectively. These findings suggest an integrative model for cerebral cortical GABAergic neuronal and OL lineage maturation that would incorporate the sequential contributions of the ventral and dorsal forebrain, and the potential role of regional developmental cues in modulating transcriptional codes within evolving neural lineage species.
During mammalian cerebral cortical development, neural stem cells (NSCs) present within periventricular generative zones give rise to successive waves of neurons and radial glia, followed by oligodendrocytes and astrocytes. The molecular and cellular mechanisms that orchestrate these precisely timed and progressive maturational events are still largely undefined. These developmental processes are likely to involve the dynamic interplay of environmental signals, cell-cell interactions and transcriptional regulatory events. The bone morphogenetic proteins (BMPs), an expanding subclass of the transforming growth factor beta cytokine superfamily, may represent an important set of environmental cues for these progressive maturational events because of the broad profiles of developmental expression of the requisite BMP ligands, receptor subunits and intracellular transduction elements, and because of their versatile roles in promoting a spectrum of cellular processes intimately involved in progressive neural fate decisions. The BMPs also interact with complementary regional environmental signals such as the basic fibroblast growth factor (bFGF) and sonic hedgehog (Shh) that promote earlier stages of NSC expansion, self-renewal, lineage restriction and incipient lineage commitment. The ability of these cytokines and trophic signals to act within specific neurodevelopmental contexts may, in turn, depend on the composite actions of cell-cell contact-associated signals, such as Notch-Hes-mediated lateral inhibitory pathways, and additional transcriptional modulatory events, such as those mediated by members of the inhibitor of differentiation (ID) gene family that encode a novel set of negative basic helix-loop-helix (bHLH) transcription factors. In this chapter, we will examine the distinct roles of these different classes of developmental cues in defining the biological properties of an integrated cerebral cortical developmental signaling network. Ongoing studies in this exciting area of mammalian central nervous system (CNS) development will help to identify important molecular and cellular targets for evolving pharmacological, gene and stem cell therapeutic interventions to combat the pathological sequelae of a spectrum of acquired and genetic disorders of the central nervous system.
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