Abstract

BackgroundNolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.ResultsHere we analyze the role of Nolz1 during LGE development. We show that Nolz1 expression is high in proliferating neural progenitor cells (NPCs) of the LGE subventricular zone. In addition, low levels of Nolz1 are detected in the mantle zone, as well as in the adult striatum. Similarly, Nolz1 is highly expressed in proliferating LGE-derived NPC cultures, but its levels rapidly decrease upon cell differentiation, pointing to a role of Nolz1 in the control of NPC proliferation and/or differentiation. In agreement with this hypothesis, we find that Nolz1 over-expression promotes cell cycle exit of NPCs in neurosphere cultures and negatively regulates proliferation in telencephalic organotypic cultures. Within LGE primary cultures, Nolz1 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 Nolz1 expression in different systems. Here we show that Nolz1 also responds to this morphogen in E12.5 LGE-derived cell cultures. However, Nolz1 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 Gsx2, which is necessary for normal RA signaling during LGE development, is also required for Nolz1 expression, which is lost in Gsx2 knockout mice. These findings suggest that Nolz1 might act downstream of Gsx2 to regulate RA-induced neurogenesis. Keeping with this hypothesis, we show that Nolz1 induces the selective expression of the RA receptor (RAR)β without altering RARα or RARγ. In addition, Nozl1 over-expression increases RA signaling since it stimulates the RA response element. This RA signaling is essential for Nolz1-induced neurogenesis, which is impaired in a RA-free environment or in the presence of a RAR inverse agonist. It has been proposed that Drosophila Gsx2 and Nolz1 homologues could cooperate with the transcriptional co-repressors Groucho-TLE to regulate cell proliferation. In agreement with this view, we show that Nolz1 could act in collaboration with TLE-4, as they are expressed at the same time in NPC cultures and during mouse development.ConclusionsNolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.

Highlights

  • Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), its function is still unknown

  • Nolz1 expression is regulated during striatal development In order to analyze whether the temporal expression pattern of Nolz1 protein resembles that of Nolz1 mRNA, a polyclonal antibody was raised against 12 amino acids of the amino terminus of the Nolz1 protein sequence (Figure 1A)

  • When cells were dissociated and plated again (P1), no differences were observed in any condition studied (Figure 4E). These findings indicate a transient effect of Nolz1 and that variation of the levels of this transcription factor does not permanently affect neural progenitor cell (NPC) populations since human Nolz (hNolz) over-expression or Nolz1 small interfering RNA (siRNA) was lost after the first passage

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Summary

Introduction

Nolz is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), its function is still unknown. During the first stages of striatal development, neurons arise from the ventricular zone (VZ), which is mainly composed of neuroepithelial cells [1,2]. Around embryonic day (E)11.5, these cells divide asymmetrically; giving rise to radial glial cells and neural progenitor cells (NPCs). Radial glial cells have extensions that contact with the ventricular lumen and with more differentiated inner zones of the developing striatum, but their cell bodies remain in the VZ [3,4,5]. The SVZ is a thin layer of cells, mainly formed of NPCs [4,6]. Striatal projecting neurons are born in the SVZ of the lateral ganglionic eminence (LGE) whereas the medial ganglionic eminence will give rise to cortical and striatal interneurons

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