A new study by Mason and colleagues, published in Development, provides strong evidence that Notch activity is crucial for neurogenesis in the basal forebrain — specifically for the generation of striatal neurons from progenitor cells in the ventricular zone.

The striatum is segregated into two distinct compartments — patches (or striosomes) and the surrounding extrastriosomal matrix — each with specific biochemical and functional profiles. During development, patch neurons generally emerge ahead of matrix neurons, although the developmental events that guide the generation of neurons in these two compartments has, until now, remained unclear.

Both Notch1 and Notch3 are expressed in progenitor cells in the forebrain, and gain-of-function studies have implicated Notch signalling in the regulation of cell fate during forebrain development. However, because mutants that lack Notch1 die before the onset of neurogenesis, it has been impossible to definitively establish the effects of Notch activity in neurogenesis or later stages of neuronal development.

To tackle this problem, Mason and co-workers used the Cre/loxP recombination system to create mice in which either Notch1 or Notch3 was selectively deleted and mice in which both Notch1 and Notch3 were eliminated. The absence of Notch1 in the telencephalon from before the onset of neurogenesis selectively impaired the development of patch neurons, whereas matrix formation remained intact.

Although a lack of Notch3 alone did not affect patch or matrix development, mice that were deficient in both Notch1 and Notch3 had a severe reduction in the number of matrix neurons. The authors therefore concluded that Notch3 functionally compensated for the absence of Notch1 in the single-knockout mutant mice to enable normal development of matrix neurons. In the double-knockout mutants, patch formation was further compromised, which indicates that Notch3 activity also influenced patch development to a limited extent in the absence of Notch1. However, as patch development was also impaired in the single-knockout mice, it seems that Notch3 could not functionally replace Notch1.

Importantly, in mice in which either Notch1 or Notch3 were deleted following progenitor cell migration from the ventricular zone in the telencephalon, development of both patch and matrix compartments in the striatum was unaffected.

These results indicate that Notch activity in progenitor cells in the ventricular zone is crucial for regulating the developmental timing that controls the generation of the distinct striatal compartments. By contrast, subsequent migration and differentiation of striatal neurons seem to proceed normally without the need for Notch activity.