<it>Ascl1 </it>is a required downstream effector of <it>Gsx </it>gene function in the embryonic mouse telencephalon

<p>Abstract</p> <p>Background</p> <p>The homeobox gene <it>Gsx2 </it>(formerly <it>Gsh2</it>) is known to regulate patterning in the lateral ganglionic eminence (LGE) of the embryonic telencephalon. In its absence, the closely related gene <it>Gsx1 </it>(previously known as <it>Gsh1</it>) can partially compensate in the patterning and differentiation of ventral telencephalic structures, such as the striatum. However, the cellular and molecular mechanisms underlying this compensation remain unclear.</p> <p>Results</p> <p>We show here that in the <it>Gsx2 </it>mutants Gsx1 is expressed in only a subset of the ventral telencephalic progenitors that normally express Gsx2. Based on the similarities in the expression of Gsx1 and Ascl1 (Mash1) within the <it>Gsx2 </it>mutant LGE, we examined whether Ascl1 plays an integral part in the <it>Gsx1</it>-based recovery. <it>Ascl1 </it>mutants show only modest alterations in striatal development; however, in <it>Gsx2;Ascl1 </it>double mutants, striatal development is severely affected, similar to that seen in the <it>Gsx1;Gsx2 </it>double mutants. This is despite the fact that <it>Gsx1 </it>is expressed, and even expands, in the <it>Gsx2;Ascl1 </it>mutant LGE, comparable to that seen in the <it>Gsx2 </it>mutant. Finally, Notch signaling has recently been suggested to be required for normal striatal development. In spite of the fact that Notch signaling is severely disrupted in <it>Ascl1 </it>mutants, it actually appears to be improved in the <it>Gsx2;Ascl1 </it>double mutants.</p> <p>Conclusion</p> <p>These results, therefore, reveal a non-proneural requirement of <it>Ascl1 </it>that together with <it>Gsx1 </it>compensates for the loss of <it>Gsx2 </it>in a subset of LGE progenitors.</p

Fbw7 controls neural stem cell differentiation and progenitor apoptosis via Notch and c-Jun

Neural stem and progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes and oligodendrocytes. However, the mechanisms underlying the decision of a stem cell to either self-renew or differentiate are incompletely understood. We demonstrate here that Fbw7 (F-box and WD repeat domain containing-7), the substrate recognition component of an SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase, is a key regulator of NSC/NPC viability and differentiation. The absence of Fbw7 in the mouse brain caused severely impaired stem cell differentiation and increased progenitor cell death. Fbw7 deficiency resulted in accumulation of two SCF(Fbw7) substrates, the transcription factors active Notch1 and N-terminally phosphorylated c-Jun. Genetic and pharmacological rescue experiments identified c-Jun as a key substrate of Fbw7 in controlling progenitor cell viability, whereas inhibition of Notch signaling alleviated the block in stem cell differentiation. Thus Fbw7 controls neurogenesis by antagonizing Notch and c-Jun N-terminal kinase (JNK)/c-Jun signaling