Mechanisms controlling striatal projection neurone generation, from patterning to early differentiation

Sammanfattning: The striatum is part of the telencephalon, the most anterior part of the vertebrate brain. From when it first can be identified, telencephalic morphology is highly complex and a wide range of mechanisms has been suggested to participate in its induction, patterning and neurogenesis. Sonic hedgehog (shh), a gene coding for a secreted protein has been suggested to be required for ventral telencephalic, including striatal, development. The first study in this thesis demonstrates that shh is important for striatal development but that aspects of this process can occur in shh mutant mice. Once the lateral ganglionic eminence (LGE, the source of striatal projection neurones) has been defined, mechanisms are required to ensure correct identity of striatal progenitor cells. The second study shows that two homeodomain transcription factor genes control aspects of this: Pax6, which is expressed in cortical progenitors and Gsh2 found in striatal progenitors. By analysing mice, mutant for either one or both of these genes, we concluded that they oppositely regulate the identity of cortical and striatal progenitors. Interestingly, we were able to demonstrate that in the absence of Gsh2, the highly similar gene Gsh1 rescues aspects of striatal development (paper III) while other aspects appear Gsh gene-independent.. When striatal neurogenesis has started, post-mitotic cells most likely rely on cell-intrinsic as well as cell-extrinsic mechanisms to ensure correct differentiation. In study four we describe the identification of candidates to the first category; homeodomain genes of the Meis and Pbx family. Finally, in the fifth study, retinoids are presented as a candidate cell-extrinsic regulator of striatal projection neurone development.