patch neurons but not late-born matrix neurons in the striatum. We further show that the late-born striatal neurons in these mutants are spared as a result of functional compensation by Notch3. Notably, however, the removal of Notch signaling subsequent to cells leaving the germinal zone has no obvious effect on striatal organization and patterning. These results indicate that Notch signaling is required in neural progenitor cells to control cell fate in the striatum, but is dispensable during subsequent phases of neuronal migration and differentiation. (Berezovska et al., 1999;Franklin et al., 1999;Redmond et al., 2000;Sestan et al., 1999). Because Notch1 null mutants die at embryonic day 9.5 (E9.5) (Conlon et al., 1995;Swiatek et al., 1994), a time prior to formation of the nervous system, it has been impossible to examine the role of Notch signaling in neurogenesis and in subsequent stages of neuronal maturation in vivo. Neural progenitor cells sequentially give rise to different types of neurons, from which it can be predicted that the loss of Notch signaling would result in the production of early cell fates at the expense of later-born cell types in the striatum, because the progenitor population would become prematurely depleted in the absence of Notch activity. However, at least one Notch receptor, Notch3, has been reported to antagonize Notch1 activity on the basis of gain-of-function experiments (Apelqvist et al., 1999;Beatus et al., 1999;Beatus et al., 2001). Notch3 null mutants are viable (Krebs et al., 2003) and display some defects in vasculogenesis (Domenga et al., 2004), but the function of Notch3 in striatal progenitor cells is at present unclear. Moreover, the requirement for Notch signaling once cells exit the VZ is unknown. Both Notch1 and RBP-J (an intracellular mediator of signaling through all Notch receptors) null mutants show signs of precocious neuronal differentiation, although RBP-J mutants display more severe defects than Notch1 null mutants, suggesting that another Notch family member may also play a role in forebrain neurogenesis (de la Pompa et al., 1997).Like Notch1, Notch3 is expressed by progenitor cells within the forebrain (Lindsell et al., 1996). To test the role of Notch1 and Notch3 receptors in regulating neurogenesis in the striatum, we have investigated the phenotypes occurring in single and compound Notch1 conditional and Notch3 null mutant animals. We used the Cre-LoxP system (Sauer and Henderson, 1988) and two different Cre-driver lines to produce two distinct conditional deletions of the Notch1 receptor. In one case, Notch1 is removed throughout the telencephalon from the beginning of neurogenesis onwards. In the second case, Notch1 is deleted only after cells have exited the VZ in the ventral telencephalon. We have assessed striatal development in Notch1 conditional; Notch3 null double mutant mice in the context of both of these Cre-driver lines.We show here that removing Notch1 in the forebrain prior to neurogenesis preferentially affects early-born neurons in the...
