A crucial role for Olig2 in white matter astrocyte development

Abstract

The mechanisms underlying astrocyte heterogeneity in the developing mouse brain are poorly understood. The bHLH transcription factor Olig2 is essential for motoneuron and oligodendrocyte formation; however, its role in astrocyte development remains obscure. During cortical development, Olig2 is transiently expressed in immature developing astrocytes at neonatal stages and is progressively downregulated in astrocytes at late postnatal stages. To assess the function of Olig2 in astrocyte formation, we conditionally ablated Olig2 in a spatiotemporally controlled manner. In the Olig2-ablated cortex and spinal cord, the formation of astrocytes in the white matter is severely compromised. Temporally controlled mutagenesis revealed that postnatal Olig2 function is required for astrocyte differentiation in the cerebral white matter. By contrast, astrocytes in the cortical gray matter are formed, but with sustained GFAP upregulation in the superficial layers. Cell type-specific mutagenesis and fate-mapping analyses indicate that abnormal astrocyte formation is at least in part attributable to the loss of Olig2 in developing astrocytes and their precursors. Thus, our studies uncover a crucial role for Olig2 in white matter astrocyte development and reveal divergent transcriptional requirements for, and developmental sources of, morphologically and spatially distinct astrocyte subpopulations.

Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

“…Mice were backcrossed with wild-type C57BL/6N mice for seven generations before crossing with C57BL/6N hGFAP-cre transgenic mice (NCI-MMHCC) to obtain GFAPcre:TrkBflox/flox conditional mutant mice and control TrkBflox/flox littermates. As reported, the GFAP-cre transgene mediates excision of LoxP-flanked sequences in GFAP-expressing cell lineages (Malatesta et al, 2003;Cai et al, 2007), and transgenesis in the hGFAP promoter has been extensively used to assess functions of spinal cord astrocytes in adult animals (Brambilla et al, 2005(Brambilla et al, , 2009b. Because loxP sites flank both transcription initiation sites and the first coding exon of the TrkB gene, all TrkB isoforms are deleted.…”

Progeny of Olig2-Expressing Progenitors in the Gray and White Matter of the Adult Mouse Cerebral Cortex

“…The transcription factor Olig2 is a necessary regulator of oligodendrocyte and motoneurons development, and Olig2-expressing cells also generate cholinergic neurons, ependymal cells, as well as some astrocytes during development (Takebayashi et al, 2002;Ligon et al, 2006a;Masahira et al, 2006;Cai et al, 2007;Ono et al, 2008). Interestingly, Olig2 is also required for the specification of NG2 ϩ cells (Ligon et al, 2006b).…”

“…Interestingly, Olig2 is also required for the specification of NG2 ϩ cells (Ligon et al, 2006b). Similar to Olig2, NG2 is also expressed in progenitors of various lineages, including oligodendrocytes and astrocytes during development (Cai et al, 2007;Zhu et al, 2008;Ono et al, 2008), as well as multipotent progenitors in the postnatal brain (Belachew et al, 2003;Aguirre et al, 2004) and possibly even neuronal progenitors in the adult cerebral cortex (Dawson et al, 2000;Dayer et al, 2005;Tamura et al, 2007).…”

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…In this setting endogenous overexpression of a glial-associated gene S100B might drive gliogenic progenitors, while the inflammatory changes from oxidative stressors would further promote a gliocentric progenitor pool. Other candidate genes such as HSA21-localized Olig1 and Olig2 are basic helix-loop-helix (bHLH) transcription factors essential for development of oligodendrocytes (Jakovcevski and Zecevic, 2005;Lu et al, 2002;Takebayashi et al, 2002;Zhou and Anderson, 2002) or astrocytes (Cai et al, 2007;Marshall et al, 2005;Ono et al, 2008); and SYNJ1 could increase astrogliosis (Herrera et al, 2009). The number of Olig1/Olig2(+) progenitors increases in the injured CNS (Arnett et al, 2004), and Olig2(+) cells preferentially differentiate into GFAP-expressing astrocytes, the main contributors to glial scars which further secrete S100B Tatsumi et al, 2008).…”