Radial Glial Identity Is Promoted by Notch1 Signaling in the Murine Forebrain

Abstract

In vertebrates, Notch signaling is generally thought to inhibit neural differentiation. However, whether Notch can also promote specific early cell fates in this context is unknown. We introduced activated Notch1 (NIC) into the mouse forebrain, before the onset of neurogenesis, using a retroviral vector and ultrasound imaging. During embryogenesis, NIC-infected cells became radial glia, the first specialized cell type evident in the forebrain. Thus, rather than simply inhibiting differentiation, Notch1 signaling promoted the acquisition of an early cellular phenotype. Postnatally, many NIC-infected cells became periventricular astrocytes, cells previously shown to be neural stem cells in the adult. These results suggest that Notch1 promotes radial glial identity during embryogenesis, and that radial glia may be lineally related to stem cells in the adult nervous system.

Notch 2 and Notch 1/3 segregate to neuronal and glial lineages of the developing olfactory epithelium

“…Continued expression of Notch 3 in OEC subpopulations postnatally suggests it could play a role in the continued expression of BLBP (which is induced by Notch 1 activation in the CNS) in OECs throughout development. These findings parallel results from studies of the CNS defects in conditional Notch 1 and Notch 3/conditional Notch 1 knockout mice, which show decreased production of radial glia and decreased expression of the Notch target gene BLBP, respectively, in the absence of one or both receptors (Gaiano et al, 2000;Anthony et al, 2005).…”

“…Notch 1 signaling can maintain the progenitor pool during embryonic neurogenesis (Gaiano et al, 2000;Yun et al, 2002;Tokunaga et al, 2004), where it activates the transcriptional repressors Hes-1 and Hes-5 (Ohtsuka et al, 1999(Ohtsuka et al, , 2001. Its role in progenitor maintenance is supported by Notch 1 mRNA expression in the embryonic ventricular zone, along with its effector Hes-5 and multiple ligands Jagged 1 and Delta-like 1 and 3.…”

A retroviral vector suitable for ultrasound image-guided gene delivery to mouse brain

“…[1][2][3][4] However, this technology has primarily been used for the study of embryonic neurogenesis, but not that of gliogenesis or adult neurogenesis. In order to exploit this technique in these areas, a high level of stable gene expression in the brains of postnatal mice is required.…”

“…Retroviral vector CE was utilized as a control in all experiments, because it has been frequently used as a gene delivery vehicle in various experiments involving the UIGD technique. [2][3][4] In the plasmid form, the genome size transcript of the retroviral vector is made from the HCMV immediate-early promoter. In transduced cells, however, the transgene is expressed from the EF1a promoter and also possibly from the MoMLV LTR.…”

“…1,2 With this technique, the effects of genes on brain development could be efficiently studied. [1][2][3][4] Furthermore, it is possible to develop animal models that overexpress or downregulate specific genes in the brain.…”