TY - JOUR
T1 - Nolz1 promotes striatal neurogenesis through the regulation of retinoic acid signaling
AU - Urbán, Noelia
AU - Martín-Ibáñez, Raquel
AU - Herranz, Cristina
AU - Esgleas, Miriam
AU - Crespo, Empar
AU - Pardo, Monica
AU - Crespo-Enríquez, Ivan
AU - Méndez-Gómez, Héctor R.
AU - Waclaw, Ronald
AU - Chatzi, Christina
AU - Álvarez, Susana
AU - Álvarez, Rosana
AU - Duester, Gregg
AU - Campbell, Kenneth
AU - de Lera, Angel R.
AU - Vicario-Abejón, Carlos
AU - Martinez, Salvador
AU - Alberch, Jordi
AU - Canals, Josep M.
N1 - Funding Information:
We would like to thank M Teresa Muñoz, Ana López and Josep Barrachina for technical assistance, and Dr Maria Calvo, Anna Bosch and Neus Abella from the confocal microscopy unit at the Serveis Científico-Tècnics (Universitat de Barcelona) for their support and advice on confocal techniques. We also thank Dr Peter Marynen (Université de Leuven, Belgium) for the pcDNA-hGsx2 construct and Dr Pantelis Tsoulfas (University of Miami, FL, USA) for the pRRLsinPPT plasmid. We thank Dr Stefano Stifani (McGill University, Montreal, Canada) for the anti-Tle4 antibody. We are also grateful to Dr A Nagy, R Nagy, Dr J Rossant, and Dr W Abramow-Newerly from the Samuel Lunenfeld Research Institute (Mont Sinai Hospital, Toronto, Canada) for the generous gift of the R1 mouse embryonic stem cell line. This study was supported by grants from the Ministerio de Ciencia e Innovación (SAF2008-04360, to JA; SAF2009-07774 and PLE2009-0089, to JMC; SAF2004-05798, to CV-A), Spain; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (CIBERNED, to JA and CV-A; and RETICS (RD06/0010/0006; Red de Terapia Celular), to JMC), Spain; the Fundació La Marató de TV3 (to JA), Spain; Generalitat de Catalunya (2009SGR-00326 to JA), Spain; and the National Institutes of Health (EY013969, to GD). The Cell Therapy Program is supported by the Centre of Regenerative Medicine in Barcelona (CMRB; Promt-0901, to JMC; Generalitat de Catalunya), Spain.
PY - 2010/8/24
Y1 - 2010/8/24
N2 - Background: Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.Results: Here 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.Conclusions: Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.
AB - Background: Nolz1 is a zinc finger transcription factor whose expression is enriched in the lateral ganglionic eminence (LGE), although its function is still unknown.Results: Here 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.Conclusions: Nolz1 promotes RA signaling in the LGE, contributing to the striatal neurogenesis during development.
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U2 - 10.1186/1749-8104-5-21
DO - 10.1186/1749-8104-5-21
M3 - Article
C2 - 20735826
AN - SCOPUS:77955807476
SN - 1749-8104
VL - 5
JO - Neural Development
JF - Neural Development
IS - 1
M1 - 21
ER -