Abstract
PAX6 is a highly conserved transcription factor and key regulator of several neurogenic processes, including the continuous generation of dopaminergic/GABAergic interneurons in the adult ventricular-subventricular (V-SVZ) neurogenic system in mice. Here we report that PAX6 cooperates with the TALE-homeodomain transcription factor PBX1 in this context. Chromatin-immunoprecipitation showed that PBX1 and PAX6 co-occupy shared genomic binding sites in adult V-SVZ stem- and progenitor cell cultures and mouse embryonic stem cells, while depletion of Pbx1 revealed that association of PAX6 with these sites requires the presence of PBX1. Expression profiling together with viral overexpression or knockdown of Pax6 or Pbx1 identified novel PBX1-PAX6 co-regulated genes, including several transcription factors. Computational modeling of genome wide expression identified novel cross-regulatory networks among these very transcription factors. Taken together, the results presented here highlight the intimate link that exists between PAX6 and TALE-HD family proteins and contribute novel insights into how the orchestrated activity of transcription factors shapes adult V-SVZ neurogenesis.
Highlights
PAX6 is a highly conserved transcription factor and key regulator of several neurogenic processes, including the continuous generation of dopaminergic/GABAergic interneurons in the adult ventricularsubventricular (V-SVZ) neurogenic system in mice
Neuroblasts born in the adult V-SVZ migrate in chains along the rostral migratory stream (RMS) into the olfactory bulb (OB), where most of them differentiate into GABAergic interneurons and integrate into existing neuronal circuits[1]
Co-immunofluorescent staining of PBX1, PAX6 and DCX on cryosections of the caudal RMS close to the V-SVZ further demonstrated widespread presence of PBX1 in DCX+ neuroblasts, some of which co-labeled for PAX6 (Fig. 1d)
Summary
PAX6 is a highly conserved transcription factor and key regulator of several neurogenic processes, including the continuous generation of dopaminergic/GABAergic interneurons in the adult ventricularsubventricular (V-SVZ) neurogenic system in mice. As soon as cells start to differentiate, MEIS2 enters the cell nucleus, joins PBX1 at the DNA and recruits the chromatin-modifying enzyme Poly(ADP-ribose)-polymerase 1 (PARP1) into the complex[9,18,19]. This leads to local chromatin decompaction and facilitates the binding of additional regulatory proteins, such as histone modifying enzymes, chromatin remodeling complexes or other transcription factors[18,20,21,22]. We used chromatinimmunoprecipitation (ChIP) and gene expression profiling to experimentally test the hypothesis that PBX1 and PAX6 cooperate in common gene regulation of adult V-SVZ progenitor cells
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