Biomedical subjects

Q Richard Lu

Publications and source records attributed to Q Richard Lu.

7 recordsLinked to original sources

PubMed2007

Insulin-like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination.

Insulin-like growth factor-I (IGF-I) has been shown to be a potent agent in promoting the growth and differentiation of oligodendrocyte precursors, and in stimulating myelination during development and following injury. To definitively determine whether IGF-I acts directly on the cells of oligodendrocyte lineage, we generated lines of mice in which the type 1 IGF receptor gene (igf1r) was conditionally ablated either in Olig1 or proteolipid protein expressing cells (termed IGF1R(pre-oligo-ko) and IGF1R(oligo-ko) mice, respectively). Compared with wild type mice, IGF1R(pre-oligo-ko) mice had a decreased volume (by 35-55%) and cell number (by 54-70%) in the corpus callosum (CC) and anterior commissure at 2 and 6 weeks of age, respectively. IGF1R(oligo-ko) mice by 25 weeks of age also showed reductions, albeit less marked, in CC volume and cell number. Unlike astrocytes, the percentage of NG2(+) oligodendrocyte precursors was decreased by approximately 13% in 2-week-old IGF1R(pre-oligo-ko) mice, while the percentage of CC1(+) mature oligodendrocytes was decreased by approximately 24% in 6-week-old IGF1R(pre-oligo-ko) mice and approximately 25% in 25-week-old IGF1R(oligo-ko) mice. The reduction in these cells is apparently a result of decreased proliferation and increased apoptosis. These results indicate that IGF-I directly affects oligodendrocytes and myelination in vivo via IGF1R, and that IGF1R signaling in the cells of oligodendrocyte lineage is required for normal oligodendrocyte development and myelination. These data also provide a fundamental basis for developing strategies with the potential to target IGF-IGF1R signaling pathways in oligodendrocyte lineage cells for the treatment of demyelinating disorders.

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PubMed2006

A critical role for dorsal progenitors in cortical myelination.

Much controversy regarding the anatomical sources of oligodendrocytes in the spinal cord and hindbrain has been resolved. However, the relative contribution of dorsal and ventral progenitors to myelination of the cortex is still a subject of debate. To assess the contribution of dorsal progenitors to cortical myelination, we ablated the basic helix-loop-helix transcription factor Olig2 in the developing dorsal telencephalon. In Olig2-ablated cortices, myelination is arrested at the progenitor stage. Under these conditions, ventrally derived oligodendrocytes migrate dorsally into the Olig2-ablated territory but cannot fully compensate for myelination deficits observed at postnatal stages. Thus, spatially restricted ablation of Olig2 function unmasks a contribution of dorsal progenitors to cortical myelination that is much greater than hitherto appreciated.

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PubMed2006

An oligodendrocyte-specific zinc-finger transcription regulator cooperates with Olig2 to promote oligodendrocyte differentiation.

Molecular mechanisms that control oligodendrocyte myelination during mammalian central nervous system (CNS) development are poorly understood. In this study, we identified Zfp488, an oligodendrocyte-specific zinc-finger transcription regulator, by screening for genes downregulated in the optic nerves of Olig1-null mice. The predicted primary structure of Zfp488 is evolutionarily conserved in vertebrates and invertebrates. In the developing CNS, Zfp488 is specifically expressed in oligodendrocytes but not their precursors. Its expression increases in parallel with that of major myelin genes Mbp and Plp1. Zfp488 is a nuclear protein that possesses transcriptional repression activity. In the developing chick neural tube, Zfp488 can promote oligodendrocyte precursor formation upon Notch activation. In addition, Zfp488 can interact and cooperate with the bHLH transcription factor Olig2 to promote precocious and ectopic oligodendrocyte differentiation. Furthermore, knockdown of Zfp488 via RNAi in an oligodendroglial cell line leads to the downregulation of myelin gene expression. Taken together, these data suggest that Zfp488 functions as an oligodendrocyte-specific transcription co-regulator important for oligodendrocyte maturation and that zinc-finger/bHLH cooperation can serve as a mechanism for oligodendroglial differentiation.

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PubMed2005

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth.

The inability of CNS axons to regenerate after traumatic spinal cord injury is due, in part, to the inhibitory effects of myelin. The three major previously identified constituents of this activity (Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein) were isolated based on their potent inhibition of axon outgrowth in vitro. All three myelin components transduce their inhibitory signals through the same Nogo receptor/p75 neurotrophin receptor/LINGO-1 (NgR1/p75/LINGO-1) complex. In this study, we considered that molecules known to act as repellants in vertebrate embryonic axonal pathfinding may also inhibit regeneration. In mice, ephrin-B3 functions during development as a midline repellant for axons of the corticospinal tract. We therefore investigated whether this repellant was expressed in the adult spinal cord and retained inhibitory activity. We demonstrate that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and, by using primary CNS neurons, show that ephrin-B3 accounts for an inhibitory activity equivalent to that of the other three myelin-based inhibitors, acting through p75, combined. Our data describe a known vertebrate axon guidance molecule as a myelin-based inhibitor of neurite outgrowth.

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PubMed2005

Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice.

Myelin-forming oligodendrocytes facilitate saltatory nerve conduction and support neuronal functions in the mammalian CNS. Although the processes of oligodendrogliogenesis and differentiation from neural progenitor cells have come to light in recent years, the molecular mechanisms underlying oligodendrocyte myelinogenesis are poorly defined. Herein, we demonstrate the pivotal role of the basic helix-loop-helix transcription factor, Olig1, in oligodendrocyte myelinogenesis in brain development. Mice lacking a functional Olig1 gene develop severe neurological deficits and die in the third postnatal week. In the brains of these mice, expression of myelin-specific genes is abolished, whereas the formation of oligodendrocyte progenitors is not affected. Furthermore, multilamellar wrapping of myelin membranes around axons does not occur, despite recognition and contact of axons by oligodendrocytes, and Olig1-null mice develop widespread progressive axonal degeneration and gliosis. In contrast, myelin sheaths are formed in the spinal cord, although the extent of myelination is severely reduced. At the molecular level, we find that Olig1 regulates transcription of the major myelin-specific genes, Mbp, Plp1, and Mag, and suppresses expression of a major astrocyte-specific gene, Gfap. Together, our data indicate that Olig1 is a central regulator of oligodendrocyte myelinogenesis in brain and that axonal recognition and myelination by oligodendrocytes are separable processes.

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PubMed2002

Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection.

The oligodendrocyte lineage genes Olig1 and Olig2 encode related bHLH proteins that are coexpressed in neural progenitors. Targeted disruption of these two genes sheds light on the ontogeny of oligodendroglia and genetic requirements for their development from multipotent CNS progenitors. Olig2 is required for oligodendrocyte and motor neuron specification in the spinal cord. Olig1 has roles in development and maturation of oligodendrocytes, evident especially within the brain. Both Olig genes contribute to neural pattern formation. Neither Olig gene is required for astrocytes. These findings, together with fate mapping analysis of Olig-expressing cells, indicate that oligodendrocytes are derived from Olig-specified progenitors that give rise also to neurons.

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PubMed2002

An 'oligarchy' rules neural development.

Recent reports show that Olig genes, which encode the basic helix-loop-helix Olig transcription factors, are essential for development of oligodendrocytes. Surprisingly, Olig function is also required for formation of somatic motor neurons. These findings alter our views of how the oligodendrocyte lineage is generated and raise further questions about the underlying developmental relationships between neurons and glia.

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