| Summary: | <p>Abstract</p> <p>Background</p> <p><it>Nolz1 </it>is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.</p> <p>Results</p> <p>Here we analyze the role of <it>Nolz1 </it>during LGE development. We show that <it>Nolz1 </it>expression is high in proliferating neural progenitor cells (NPCs) of the LGE subventricular zone. In addition, low levels of <it>Nolz1 </it>are detected in the mantle zone, as well as in the adult striatum. Similarly, <it>Nolz1 </it>is highly expressed in proliferating LGE-derived NPC cultures, but its levels rapidly decrease upon cell differentiation, pointing to a role of <it>Nolz1 </it>in the control of NPC proliferation and/or differentiation. In agreement with this hypothesis, we find that <it>Nolz1 </it>over-expression promotes cell cycle exit of NPCs in neurosphere cultures and negatively regulates proliferation in telencephalic organotypic cultures. Within LGE primary cultures, <it>Nolz1 </it>over-expression promotes the acquisition of a neuronal phenotype, since it increases the number of β-III tubulin (Tuj1)- and microtubule-associated protein (MAP)2-positive neurons, and inhibits astrocyte generation and/or differentiation. Retinoic acid (RA) is one of the most important morphogens involved in striatal neurogenesis, and regulates <it>Nolz1 </it>expression in different systems. Here we show that <it>Nolz1 </it>also responds to this morphogen in E12.5 LGE-derived cell cultures. However, <it>Nolz1 </it>expression is not regulated by RA in E14.5 LGE-derived cell cultures, nor is it affected during LGE development in mouse models that present decreased RA levels. Interestingly, we find that <it>Gsx2</it>, which is necessary for normal RA signaling during LGE development, is also required for <it>Nolz1 </it>expression, which is lost in <it>Gsx2 </it>knockout mice. These findings suggest that <it>Nolz1 </it>might act downstream of <it>Gsx2 </it>to regulate RA-induced neurogenesis. Keeping with this hypothesis, we show that <it>Nolz1 </it>induces the selective expression of the RA receptor (RAR)β without altering RARα or RARγ. In addition, <it>Nozl1 </it>over-expression increases RA signaling since it stimulates the RA response element. This RA signaling is essential for <it>Nolz1</it>-induced neurogenesis, which is impaired in a RA-free environment or in the presence of a RAR inverse agonist. It has been proposed that <it>Drosophila Gsx2 </it>and <it>Nolz1 </it>homologues could cooperate with the transcriptional co-repressors Groucho-TLE to regulate cell proliferation. In agreement with this view, we show that <it>Nolz1 </it>could act in collaboration with TLE-4, as they are expressed at the same time in NPC cultures and during mouse development.</p> <p>Conclusions</p> <p><it>Nolz1 </it>promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.</p>
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