Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin–proteosome system

Tuoc, Tran; Stoykova, Anastassia

doi:10.1101/gad.471708

Cited by 102 publications

(95 citation statements)

References 52 publications

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“…Intriguingly, the elimination of Pax6 function after the generation of IGL neurons did not affect either the specification or the number of the resulting SGL neuronal lineages. During the progression of neuronal differentiation, Pax6 expression strongly declines after E14.5 at both the transcriptional and translational level (Tuoc and Stoykova, 2008b). Together, these findings suggest that the low level of Pax6 in late RGPs does not play an important role in the specification of SGL versus IGL neuronal fate.…”

Section: Absence Of Pax6 Causes Sgl Dysgenesis But Does Not Affect Thsupporting

confidence: 53%

Selective Cortical Layering Abnormalities and Behavioral Deficits in Cortex-Specific Pax6 Knock-Out Mice

Tuoc

Radyushkin

Tonchev³

et al. 2009

Journal of Neuroscience

103

107

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The transcription factor Pax6 has been implicated in neocortical neurogenesis in vertebrates, including humans. Analyses of the role of Pax6 in layer formation and cognitive abilities have been hampered by perinatal lethality of Pax6 mutants. Here, we generated viable mutants exhibiting timed, restricted inactivation of Pax6 during early and late cortical neurogenesis using Emx1-Cre and hGFAP-Cre lines, respectively. The disruption of Pax6 at the onset of neurogenesis using Emx1-Cre line resulted in premature cell cycle exit of early progenitors, increase of early born neuronal subsets located in the marginal zone and lower layers, and a nearly complete absence of upper layer neurons, especially in the rostral cortex. Furthermore, progenitors, which accumulated in the enlarged germinal neuroepithelium at the pallial/subpallial border in the Pax6 mutants, produced an excess of oligodendrocytes. The inactivation of Pax6 after generation of the lower neuronal layers using hGFAP-Cre line did not affect specification or numbers of late-born neurons, indicating that the severe reduction of upper layer neurons in Pax6 deficiency is mostly attributable to a depletion of the progenitor pool, available for late neurogenesis. We further show that Pax6 fl/fl ;Emx1-Cre mutants exhibited deficiencies in sensorimotor information integration, and both hippocampus-dependent short-term and neocortex-dependent long-term memory recall. Because a majority of the morphological and behavior disabilities of the Pax6 mutant mice parallel abnormalities reported for aniridia patients, a condition caused by PAX6 haploinsufficiency, the Pax6 conditional mutant mice generated here represent a valuable genetic tool to understand how the developmental cortical disruption can lead to a human behavior abnormality.

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Section: Absence Of Pax6 Causes Sgl Dysgenesis But Does Not Affect Thsupporting

confidence: 53%

Selective Cortical Layering Abnormalities and Behavioral Deficits in Cortex-Specific Pax6 Knock-Out Mice

Tuoc

Radyushkin

Tonchev³

et al. 2009

Journal of Neuroscience

103

107

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“…50,51 The following polyclonal (pAb) and monoclonal (mAb) primary antibodies used in this study were obtained from the indicated commercial sources: Brg1 rabbit pAb (Santa Cruz), Brg1 mouse mAb (Santa Cruz), Brm mouse mAb (BD Biosciences), Brm rabbit pAb (Abcam), BAF250 mouse mAb (Sigma), BAF170 rabbit pAb (Bethyl), BAF170 rabbit pAb (Sigma), BAF155 rabbit pAb (Santa Cruz), BAF155 mouse mAb (Santa Cruz), BAF60a mouse mAb (BD Biosciences), GAPDH rabbit pAb (Santa Cruz), ß-actin rabbit pAb (Sigma), and H3K27me3 rabbit pAb (Upstate). The utilized secondary antibodies included peroxidase-conjugated goat anti-rabbit IgG (1:10,000; Covance), peroxidase-conjugated goat anti-mouse IgG (1:5000; Covance), and Alexa 488-or Alexa 568-conjugated IgG (various species,1: 400; Molecular Probes).…”

Section: Immunohistochemistry (Ihc) and Western Blotting (Wb)mentioning

confidence: 99%

“…Densitometric quantification of WB bands and quantitative analysis of IHC signal intensities were performed using the ImageJ software, as described previously. 21,51 Statistical analyses were carried out using the Student's t-test. The results are presented as the mean § SEM.…”

Section: Imaging and Quantitative And Statistical Analysesmentioning

confidence: 99%

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

et al. 2016

Self Cite

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The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.

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“…These isoforms vary from each other in their Nterminal structures. The common p46 isoform has a 128-amino acid PD at the N terminus and a 56-amino acid HD in the central region which bind specifically to different DNA sequences, P6CON and P3 (TAAT/ATTA), respectively (12)(13)(14). At the C terminus, a conserved domain rich in proline (P), serine (S), and threonine (T) residues exists in all Pax-6 isoforms and thus is named the "PST" domain ( Fig.…”

mentioning

confidence: 99%

Sumoylation activates the transcriptional activity of Pax-6, an important transcription factor for eye and brain development

Yan¹,

Gong²,

Deng³

et al. 2010

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

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Pax-6 is an evolutionarily conserved transcription factor regulating brain and eye development. Four Pax-6 isoforms have been reported previously. Although the longer Pax-6 isoforms (p46 and p48) bear two DNA-binding domains, the paired domain (PD) and the homeodomain (HD), the shorter Pax-6 isoform p32 contains only the HD for DNA binding. Although a third domain, the proline-, serineand threonine-enriched activation (PST) domain, in the C termini of all Pax-6 isoforms mediates their transcriptional modulation via phosphorylation, how p32 Pax-6 could regulate target genes remains to be elucidated. In the present study, we show that sumoylation at K91 is required for p32 Pax-6 to bind to a HD-specific site and regulate expression of target genes. First, in vitro-synthesized p32 Pax-6 alone cannot bind the P3 sequence, which contains the HD recognition site, unless it is preincubated with nuclear extracts precleared by anti-Pax-6 but not by anti-small ubiquitin-related modifier 1 (anti-SUMO1) antibody. Second, in vitro-synthesized p32 Pax-6 can be sumoylated by SUMO1, and the sumoylated p32 Pax-6 then can bind to the P3 sequence. Third, Pax-6 and SUMO1 are colocalized in the embryonic optic and lens vesicles and can be coimmunoprecipitated. Finally, SUMO1-conjugated p32 Pax-6 exists in both the nucleus and cytoplasm, and sumoylation significantly enhances the DNA-binding ability of p32 Pax-6 and positively regulates gene expression. Together, our results demonstrate that sumoylation activates p32 Pax-6 in both DNA-binding and transcriptional activities. In addition, our studies demonstrate that p32 and p46 Pax-6 possess differential DNA-binding and regulatory activities.retina | lens | cataract | small eye mutation | pancreas

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Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin–proteosome system

Abstract: [Keywords: Cortex; neurogenesis; Pax6; ubiquitin-proteosome system] Supplemental material is available at http://www.genesdev.org.

Cited by 102 publications

References 52 publications

Selective Cortical Layering Abnormalities and Behavioral Deficits in Cortex-Specific Pax6 Knock-Out Mice

Selective Cortical Layering Abnormalities and Behavioral Deficits in Cortex-Specific Pax6 Knock-Out Mice

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

Sumoylation activates the transcriptional activity of Pax-6, an important transcription factor for eye and brain development

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