Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube

Abstract

Astrocytes are the most abundant and functionally diverse glial population in the vertebrate central nervous system (CNS). However, the mechanisms underlying astrocyte specification are poorly understood. It is well established that cellular diversification of neurons in the embryo is generated by position-dependent extrinsic signals and combinatorial interactions of transcription factors that direct specific cell fates by suppressing alternative fates. It is unknown whether a comparable process determines embryonic astrocyte identity. Indeed, astrocyte development is generally thought to take place in a position-independent manner. Here we show multiple functions of Stem cell leukaemia (Scl, also known as Tal1), which encodes a basic helix-loop-helix (bHLH) transcription factor, in the regulation of both astrocyte versus oligodendrocyte cell fate acquisition and V2b versus V2a interneuron cell fate acquisition in the p2 domain of the developing vertebrate spinal cord. Our findings demonstrate a regionally restricted transcriptional programme necessary for astrocyte and V2b interneuron development, with striking parallels to the involvement of SCL in haematopoiesis. They further indicate that acquisition of embryonic glial subtype identity might be regulated by genetic interactions between SCL and the transcription factor Olig2 in the ventral neural tube.

Transforming growth factor α promotes sequential conversion of mature astrocytes into neural progenitors and stem cells

“…Lack of Olig2 expression in control cultures further supports astrocyte maturity and initial lack of progenitors. Indeed, whereas mature astrocytes lack Olig2 expression, this transcription factor is present in radial glial cells, glial-restricted progenitors and immature astrocytes (Marshall et al, 2005), and its expression has been shown to repress astrocytes differentiation (Fukuda et al, 2004;Muroyama et al, 2005). Serum starvation of the cultures prior growth factors addition, and possibly the repeated washes with ice-cold phosphate saline buffer initially designed to remove the microglial and oligodendroglial cells, which reside at the top of the cellular layer, might account for the lack of neural progenitors and stem cells in our astrocyte cultures.…”

“…Olig2 inhibits the differentiation of neural progenitors into astrocytes (Fukuda et al, 2004;Muroyama et al, 2005) and its expression is downregulated in vitro and in vivo in mature astrocytes (Fukuda et al, 2004;Marshall et al, 2005). Accordingly, a hardly detectable Olig2-immunoreactive signal was observed in control astrocytes (Figure 2g), whereas TGFa-treated cells exhibited a strong nuclear Olig2-immunoreactive signal (Figure 2h).…”

Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube

“…R. Soc. B (2008) oligodendrocyte generation (Muroyama et al 2005). Thus, the opponent activities of Olig2 and Scl together with the Notch signalling pathway and other timing mechanisms may account for how distinct neuronal and glial cell types are generated in both a spatially and a temporally organized manner.…”

“…Insight into this process has recently been made through studies of the function of the bHLH protein Scl in the ventral spinal cord. Early in development, Scl is expressed by neural progenitors that give rise to a subset of V2 interneurons (Smith et al 2002;Muroyama et al 2005). However, at later times, the production of V2 interneurons ceases and Scl C cells transform into astrocyte progenitors (Muroyama et al 2005).…”

“…Early in development, Scl is expressed by neural progenitors that give rise to a subset of V2 interneurons (Smith et al 2002;Muroyama et al 2005). However, at later times, the production of V2 interneurons ceases and Scl C cells transform into astrocyte progenitors (Muroyama et al 2005). In a manner analogous to Olig2, Scl appears to be both necessary and sufficient to direct the formation of V2 interneurons and astrocytes, which may be attributed to its ability to extinguish the expression of Olig2 and thereby suppress MN and Ventral neural tube patterning J.…”