Transcription Factor Expression and Notch-Dependent Regulation of Neural Progenitors in the Adult Rat Spinal Cord

Abstract

Recent studies have demonstrated that neural stem cells and other progenitors are present in the adult CNS. Details of their properties, however, remain poorly understood. Here we examined the properties and control mechanisms of neural progenitors in the adult rat spinal cord at the molecular level. Adult and embryonic progenitors commonly expressed various homeodomain-type (Pax6, Pax7, Nkx2.2, and Prox1) and basic helix-loop-helix (bHLH)-type (Ngn2, Mash1, NeuroD1, and Olig2) transcriptional regulatory factors in vitro. Unlike their embryonic counterparts, however, adult progenitors could not generate specific neurons that expressed markers appropriate for spinal motoneurons or interneurons, including Islet1, Lim1, Lim3, and HB9. Cells expressing the homeodomain factors Pax6, Pax7, and Nkx2.2 also emerged in vivo in response to injury and were distributed in unique patterns in the lesioned spinal cord. However, neither the expression of the neurogenic bHLH factors including Ngn2, Mash1, and NeuroD1 nor subsequent generation of new neurons could be detected in injured tissue. Our results suggest that signaling through the cellsurface receptor Notch is involved in this restriction. The expression of Notch1 in vivo was enhanced in response to injury. Furthermore, activation of Notch signaling in vitro inhibited differentiation of adult progenitors, whereas attenuation of Notch signals and forced expression of Ngn2 significantly enhanced neurogenesis. These results suggest that both the intrinsic properties of adult progenitors and local environmental signals, including Notch signaling, account for the limited regenerative potential of the adult spinal cord.

Expression pattern of the transcription factor Olig2 in response to brain injuries: Implications for neuronal repair

“…Next, we characterized the identity of cells expressing Olig2 (see Table 1, which is published as supporting information on the PNAS web site, for cell type identification criteria). In the intact adult CNS, Olig2 is expressed in mature oligodendrocytes and NG2-positive glial precursors (30)(31)(32). Consistent with these data, the majority of NG2-positive (NG2ϩ) cells in the intact cortical GM (Ϸ70%) contained Olig2, but they only accounted for 26% of the Olig2ϩ cell pool (Fig.…”

“…Indeed, here we could show that antagonizing Olig2 function after stab lesion enabled a small, but significant, number of infected cells to generate neuroblasts. Because many antineurogenic factors are released upon acute brain injury (30,(48)(49)(50), the small number of neuroblasts is no surprise. However, these data show as a proof-of-principle that suppression of antineurogenic determinants allows the progression of at least some precursors in the adult lesioned mammalian cortex toward a neurogenic fate.…”

Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain

“…This situation can be improved after transduction with potent neurogenic transcription factors (8,24), but the response is still rather limited. Obviously the antineurogenic environment present in the adult brain parenchyma (38) contributes to the predominant glial fate in vivo, with Notch (39) and BMP signaling (40) acting as potential candidates for this fate restriction. In addition, our results now suggest that the limited neurogenic response even after overexpression of neurogenic factors may also be due to targeting glial cells with less plasticity than the multipotent subset of reactive astrocytes.…”

Autopsy verifies demyelination and lack of vascular damage in partially reversible radiation myelopathy

“…Recent studies have revealed that many regions of the adult CNS contain neuronal progenitors that have the ability to generate new neurones and glia. [34][35][36] Several adult CNS regions exhibit neurotropic-factor responsiveness, including the spinal cord. 37 Nieder et al 38 surveyed data relating to the pathogenesis of radiation myelopathy and suggested that the administration of cytokines could increase the proliferation of oligodendrocyte progenitors, upregulate the synthesis of myelin constituents and promote myelin regeneration in the adult CNS.…”