Ascl1 is a required downstream effector of Gsx gene function in the embryonic mouse telencephalon.

BACKGROUND: The homeobox gene Gsx2 (formerly Gsh2) is known to regulate patterning in the lateral ganglionic eminence (LGE) of the embryonic telencephalon. In its absence, the closely related gene Gsx1 (previously known as Gsh1) 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. RESULTS: We show here that in the Gsx2 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 Gsx2 mutant LGE, we examined whether Ascl1 plays an integral part in the Gsx1-based recovery. Ascl1 mutants show only modest alterations in striatal development; however, in Gsx2;Ascl1 double mutants, striatal development is severely affected, similar to that seen in the Gsx1;Gsx2 double mutants. This is despite the fact that Gsx1 is expressed, and even expands, in the Gsx2;Ascl1 mutant LGE, comparable to that seen in the Gsx2 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 Ascl1 mutants, it actually appears to be improved in the Gsx2;Ascl1 double mutants. CONCLUSION: These results, therefore, reveal a non-proneural requirement of Ascl1 that together with Gsx1 compensates for the loss of Gsx2 in a subset of LGE progenitors.

Molecular identity of olfactory bulb interneurons: transcriptional codes of periglomerular neuron subtypes.

Interneurons in the glomerular layer (GL) of the olfactory bulb represent a diverse set of cells, which can be identified by distinct expression of different neurotransmitters as well as calcium binding proteins. Using genetic based fate mapping, we show here that at least three of these different interneurons subtypes (i.e. dopaminergic, calbindin- and calretinin-expressing) derive from cells that express the homeobox genes Dlx5/6. The transcription factors ER81, Meis2, Pax6 and Sp8 have all been implicated in olfactory bulb interneuron development and each of these can be observed in Dlx5/6-derived periglomerular cells. Conversely, the T-box factors Tbr1 and Tbx21, which mark olfactory bulb projection neurons, are not expressed in the Dlx5/6-derived periglomerular cells. While the interneuron subtypes that are marked by Pax6 and Sp8 have been described, little information exists as to the specific subtypes that express ER81 or Meis2. We show here that ER81 is expressed in dopaminergic cells and in a subset of calretinin-expressing cells in the GL. Meis2 is found in dopaminergic and calbindin-expressing cells as well as in a subpopulation of the calretinin-expressing interneurons of the glomerular layer. These findings suggest that distinct transcriptional codes may underlie the differentiation of specific olfactory bulb interneuron subtypes.

The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons.

The molecular mechanisms that regulate the production and diversity of olfactory bulb interneurons remain poorly understood. With the exception of the GABAergic/dopaminergic subtype in the glomerular layer, no information exists concerning the generation of the other subtypes. Here we show that the recently identified zinc finger transcription factor Sp8 is expressed in neurogenic regions, which give rise to olfactory bulb interneurons at embryonic and postnatal time points and remains expressed in the calretinin-expressing and GABAergic/nondopaminergic interneurons of the glomerular layer. Conditional inactivation of Sp8 in the embryonic ventral telencephalon reveals a requirement for the normal generation of these interneuron subtypes. Sp8 conditional mutants exhibit an increase in cell death within the lateral ganglionic eminence and rostral migratory stream. Moreover, mutant neuroblasts/interneurons are misspecified and display abnormal migration patterns in the olfactory bulb, indicating that Sp8 contributes to olfactory bulb interneuron diversity by regulating the survival, migration, and molecular specification of neuroblasts/interneurons.