Title:
Progenitor heterogeneity in the developing neocortex regulated by the Notch and NF- κB signaling

Ken-ichi Mizutani, Ph.D.
Associate Professor, Brain Development and Aging Research Center , Doshisha University , and PRESTO-JST

Abstract:
The regulation of cell fate specification in the mammalian brain is poorly understood. While it is widely accepted that there are different proliferative neural cell types, little is known about how they are generated, nor how their character is differentially regulated.
The canonical signaling pathway known to generate heterogeneity in an otherwise homogeneous pool is that of Notch. As such, this pathway is an excellent candidate to generate neural progenitor heterogeneity, and by extension to be differentially utilized by distinct progenitor subtypes. However, until now it has not been easy to directly address this issue. Fortunately, we have developed a transgenic Notch reporter mouse line that has permitting us to do just that. Using both transgenic and transient in vivo reporter assays we show that (1) both radial glial stem cells (RGSCs) and intermediate neural progenitors (INPs) respond to Notch receptor activation, but that RGSCs signal through the canonical Notch effector C-promoter binding factor 1 (CBF1), whereas INPs have attenuated CBF1 signaling, (2) RGSCs and INPs coexist in the telencephalic ventricular zone (VZ) and that they can be prospectively separated on the basis of CBF1 activity, and (3) INPs are predominantly neurogenic, whereas RGSCs generate neurons, astrocytes and oligodendrocytes at similar frequencies.
More recently, we have examined the role of NF-κB signaling in embryonic neocortex, and have found that (4) NF-κB signaling promotes RGSCs character in the VZ, and intermediate progenitor character in the subventricular zone (SVZ). Interestingly, (5) pathway activation biased progenitors toward SVZ fate, consistent with the observation that endogenous NF-κB activity is widely present throughout the SVZ.
These preliminary data regarding progenitor heterogeneity in the developing neocortex, based upon differential Notch and NF-κB signaling may be an important mechanism utilized to distinguish between stem and progenitor cell subtypes.

References:
Mizutani K et al., Nature 2007;449(7160):351-355.
Mizutani K et al., Development 2005;132(6):1295-1304.