Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

Walcher, Tessa; Xie, Qing; Sun, Jian; Irmler, Martin; Beckers, Johannes; Öztürk, Timucin; Niessing, Dierk; Stoykova, Anastassia; Cvekl, Aleš; Ninkovic, Jovica; Götz, Magdalena

doi:10.1242/dev.082875

Cited by 68 publications

(85 citation statements)

References 93 publications

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“…This observation directly supports our model that Ey/Toy control growth of the eye-antennal disc and is consistent with studies in vertebrates that demonstrate roles for Pax6 in the proliferation of neural progenitors within the brain (53,(78)(79)(80). Earlier studies observed cells undergoing apoptosis in Pax6 singlemutant eye-antennal discs and showed that blocking cell death alone can partially rescue the head defects of the ey D and toy hdl mutants (46).…”

Section: Discussionsupporting

confidence: 91%

“…Our results indicate that Ey and Toy promote proliferation of the eye-antennal disc and specification of the eye, while simultaneously repressing alternate nonocular fates. These results are consistent with a previous report showing that Pax6 is also required for the development of nonocular head structures in the flour beetle, Tribolium castaneum (51), and there is growing evidence in several systems that Pax6 promotes cell proliferation (52)(53)(54)(55). These observations suggest that the function of Pax6 has been conserved across 500 million years of animal development.…”

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confidence: 93%

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Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation

Zhu

Palliyil

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Paired box 6 (Pax6) is considered to be the master control gene for eye development in all seeing animals studied so far. In vertebrates, it is required not only for lens/retina formation but also for the development of the CNS, olfactory system, and pancreas. Although Pax6 plays important roles in cell differentiation, proliferation, and patterning during the development of these systems, the underlying mechanism remains poorly understood. In the fruit fly, Drosophila melanogaster, Pax6 also functions in a range of tissues, including the eye and brain. In this report, we describe the function of Pax6 in Drosophila eye-antennal disc development. Previous studies have suggested that the two fly Pax6 genes, eyeless (ey) and twin of eyeless (toy), initiate eye specification, whereas eyegone (eyg) and the Notch (N) pathway independently regulate cell proliferation. Here, we show that Pax6 controls eye progenitor cell survival and proliferation through the activation of teashirt (tsh) and eyg, thereby indicating that Pax6 initiates both eye specification and proliferation. Although simultaneous loss of ey and toy during early eye-antennal disc development disrupts the development of all head structures derived from the eye-antennal disc, overexpression of N or tsh in the absence of Pax6 rescues only antennal and head epidermis development. Furthermore, overexpression of tsh induces a homeotic transformation of the fly head into thoracic structures. Taking these data together, we demonstrate that Pax6 promotes development of the entire eye-antennal disc and that the retinal determination network works to repress alternative tissue fates, which ensures proper development of adult head structures.Pax6 | eyeless | twin of eyeless | eye-antennal disc | Drosophila

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Section: Discussionsupporting

confidence: 91%

supporting

confidence: 93%

Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation

Zhu

Palliyil

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…1) and chromatin immunoprecipitation experiments, it was demonstrated that distinct downstream target genes were preferentially bound by either subdomain in vivo and that the PAI subdomain has a role in decreasing cell mitoses while the RED domain has the opposite effect. It was concluded that the coactivation of both proliferative and anti-proliferative genes acts to fine-tune cell-cycle progression (Walcher et al, 2013). This supposition is supported by the finding that Pax6 directs cortical cell cycle progression in a regionally specific manner (Mi et al, 2013) and that it does so through simultaneous expression of downstream target gene sets through epigenetic regulation of chromatin condensation in interaction with dynamically competitive BAF subunits during the progression of neurogenesis (Tuoc et al, 2013).…”

Section: Pax6-mediated Control Of Neurogenic Proliferation and Differmentioning

confidence: 99%

Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. KEY WORDS: Pax genes, Embryogenesis, Lineage determination IntroductionPaired box (Pax) genes encode transcription factors that contain a highly conserved DNA-binding domain called the paired domain (PD, Fig. 1A) and can be considered to be a principle regulator of gene expression. Nine Pax genes (Pax1-Pax9) have been characterised in mammals and the evolutionary conserved paired domain has been identified across phylogenies from insects, to amphibians and birds. In higher vertebrates, PAX proteins are subclassified into groups according to inclusion of an additional DNA-binding homeodomain and/or an octapeptide region, which serves as a binding motif for protein co-factors for potent inhibition of downstream gene transcription (Eberhard et al., 2000) (Fig. 1B); all PAX proteins include a transactivation domain located within the C-terminal amino acids (Underhill, 2012). It is also known that all Pax genes, with the exception of Pax4 and Pax9, produce alternative RNA transcripts (see Table 1). The functional diversity of Pax proteins in vivo is thus linked to the ability to produce alternatively spliced gene products that differ in structure and, consequently, in the binding activity of their paired and homeodomain DNA-binding regions (Underhill, 2012).Three decades ago, the characterisation and roles of Pax genes in embryonic development began to unfold. Early studies discovered that regulatory gene families such as the Pax family are involved in the sequential compartmentalisation and body patterning of developing organisms; thereafter, studies highlighted a role for Pax genes in the early specification of cell fate and the subsequent morphogenesis of various tissues and organs. Following this, mutational studies of Pax genes confirmed the importance of these regulatory roles in the PRIMER School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.*Author for correspondence (j.blake@ecu.edu.au) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.initiation and progression of ...

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“…Canonical Pax6[Pax6(−5a)] binds DNA primarily through the N-terminal portion of the paired domain (the PAI-domain), in Pax6(+5a) the DNA-binding potential of the C-terminal RED-domain predominates, whereas the 'paired-less' isoform utilizes the homeodomain for DNA binding (Epstein et al, 1994;Kleinjan et al, 2004;Kozmik et al, 1997;Mishra et al, 2002). All three isoforms recognize distinct DNA consensus sites and participate in the regulation of different developmental processes (Epstein et al, 1994;Haubst et al, 2004;Singh et al, 2002;Walcher et al, 2013). As we show here, all three isoforms can directly associate with Meis2.…”

Section: Multi-protein Network Involving Meis Family Members In the mentioning

confidence: 99%

Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb

et al. 2014

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Meis homeodomain transcription factors control cell proliferation, cell fate specification and differentiation in development and disease. Previous studies have largely focused on Meis contribution to the development of non-neuronal tissues. By contrast, Meis function in the brain is not well understood. Here, we provide evidence for a dual role of the Meis family protein Meis2 in adult olfactory bulb (OB) neurogenesis. Meis2 is strongly expressed in neuroblasts of the subventricular zone (SVZ) and rostral migratory stream (RMS) and in some of the OB interneurons that are continuously replaced during adult life. Targeted manipulations with retroviral vectors expressing function-blocking forms or with small interfering RNAs demonstrated that Meis activity is cell-autonomously required for the acquisition of a general neuronal fate by SVZ-derived progenitors in vivo and in vitro. Additionally, Meis2 activity in the RMS is important for the generation of dopaminergic periglomerular neurons in the OB. Chromatin immunoprecipitation identified doublecortin and tyrosine hydroxylase as direct Meis targets in newly generated neurons and the OB, respectively. Furthermore, biochemical analyses revealed a previously unrecognized complex of Meis2 with Pax6 and Dlx2, two transcription factors involved in OB neurogenesis. The full proneurogenic activity of Pax6 in SVZ derived neural stem and progenitor cells requires the presence of Meis. Collectively, these results show that Meis2 cooperates with Pax6 in generic neurogenesis and dopaminergic fate specification in the adult SVZ-OB system. KEY WORDS: Pax6, TALE-homeodomain proteins, Adult neurogenesis, Subventricular zone, Mouse INTRODUCTIONThe subventricular zone (SVZ), located between the lateral ventricle and the striatum, and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus are major stem cell niches in the adult

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Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

Cited by 68 publications

References 93 publications

Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation

Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation

Pax genes: regulators of lineage specification and progenitor cell maintenance

Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb

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