Sonic Hedgehog and BMP2 Exert Opposing Actions on Proliferation and Differentiation of Embryonic Neural Progenitor Cells

Abstract

Although Sonic Hedgehog (Shh) plays a critical role in brain development, its actions on neural progenitor cell proliferation and differentiation have not been clearly defined. Transcripts for the putative Shh-receptor genes patched (Ptc) and smoothened (Smo) are expressed by embryonic, postnatal, and adult progenitor cells, suggesting that Shh can act directly on these cells. The recombinant human amino-terminal fragment of Shh protein (Shh-N) alone did not support the survival of cultured progenitor cells, but treatment with Shh-N in the presence of bFGF increased progenitor cell proliferation. Furthermore, treatment of embryonic rat progenitor cells propagated either in primary culture or after mitogen expansion significantly increased the proportions of both beta-tubulin- (neuronal marker) and O4- (oligodendroglial marker) immunoreactive cells and reduced the proportion of nestin- (uncommitted neural progenitor cell marker) immunoreactive cells. By contrast Shh-N had no effect on the elaboration of GFAP- (astroglial marker) immunoreactive cells. Cotreatment with Shh-N and bone morphogenetic protein-2 (BMP2) inhibited the anti-proliferative, astroglial-inductive, and oligodendroglial-suppressive effects of BMP2. Our observations suggest that Shh-N selectively promotes the elaboration of both neuronal and oligodendroglial lineage species and inhibits the effects of BMP2 on progenitor cell proliferation and astroglial differentiation.

FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway

“…The absence of oligodendrocytes in our study following cotreatment with FGF2 and BMP4 is consistent with reports of BMPs suppressing oligodendrocyte differentiation from neural precursors (Zhu et al, 1999). The comparable levels of expression of BMP4 in primary (uncultured) and FGF-treated cultures, and the dose-response nature of BMP4 suppression of oligodendrocytes, is compatible with a balance between inductive and negative signalling requirements for oligodendrogenesis in our system.…”

“…In view of the known effect of BMPs on astroglial differentiation of neural precursors, we also examined expression of GFAP, a marker of astrocytes (Gross et al, 1996;Mabie et al, 1999;Zhu et al, 1999). To our surprise, BMP4-treated cultures contained reduced numbers of astrocytes, in contrast to cultures treated with FGF2 alone (Fig.…”

Epithelial Stem Cells and Their Niche: There's No Place Like Home

“…The Hh gene is involved in various aspects of embryonic development such as left-right asymmetry, anterior-posterior patterning of the limb bud, and neural tube formation [82][83][84]. In vertebrates, there are three Hh genes that share similar homology; Shh, Ihh, and Desert hedgehog (Dhh).…”

Mammalian Neural Stem-Cell Renewal: Nature versus Nurture

“…Overexpression of Shh at E 10 in the dorsal tube of transgenic mice, after the dorsoventral patterning of the CNS, provokes a blocking of SVZ neuroepithelial cells in a non-differentiated state (89), suggesting that Shh may prevent differentiation of neural stem cells, or derived progenitors. In support of these observations, Shh stimulates in vitro the proliferation of neural progenitors of the retina (90) or the telencephalon (91). However, whether stem cells are included in the pool of proliferating cells is unclear.…”