Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse

Tyas, David A.; Simpson, T. Ian; Carr, Catherine B.; Kleinjan, Dirk A.; Heyningen, Veronica van; Mason, John O.; Price, David J.

doi:10.1186/1471-213x-6-21

Cited by 30 publications

(34 citation statements)

References 45 publications

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“…We found that tau-GFP reporter expression in the forebrain and eye of two transgenic lines (DTy54 and Y223) carrying full-length reporter YAC transgenes derived from Y593 largely resembled that of Pax6, in agreement with previous studies [30,38]. However, close examination of tau-GFP and endogenous Pax6 expression at the cellular level highlighted some interesting differences.…”

Section: Discussionsupporting

confidence: 90%

“…DTy54 transgenic mice carry a single copy of YAC 1123, which is a full-length version of YAC 593 modified so that it expresses tau-tagged GFP instead of PAX6 (summarized in the upper part of Figure 1B) [38]. To compare expression of the tau-GFP reporter and endogenous Pax6, coronal sections along the rostral–caudal axis were double-immunolabeled for tau-GFP and Pax6 protein.…”

Section: Resultsmentioning

confidence: 99%

“…To compare expression of the tau-GFP reporter and endogenous Pax6, coronal sections along the rostral–caudal axis were double-immunolabeled for tau-GFP and Pax6 protein. Whereas staining for Pax6 is nuclear, tau-GFP binds to the microtubule component of the cytoskeleton and labels the cytoplasm [38,40]. …”

Section: Resultsmentioning

confidence: 99%

“…YAC transgenic mouse lines DTy54, Y223, Y001 and Y001ΔDRR were hemizygous for the tau-GFP reporter YAC transgene and were maintained on a CD1 background. Transgenic animals were identified by PCR for the reporter transgene as described previously [38] and embryos were genotyped by detecting GFP fluorescence. …”

Section: Methodsmentioning

confidence: 99%

“…In these transgenic lines, the GFP reporter cassette is inserted at the PAX6 translational start site in exon 4 (Figure 1B). GFP expression is, therefore, under the control of those PAX6 regulatory elements contained within the YAC transgene and is independent of the endogenous mouse Pax6 locus [30,31,38]. Previous analyses of these lines did not examine the detailed expression patterns of the transgenes in sub-regions of the eye and brain.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Genomic Regions Regulating Pax6 Expression in Embryonic Forebrain Using YAC Reporter Transgenic Mouse Lines

Huang

Kleinjan

et al. 2013

PLoS ONE

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The transcription factor Pax6 is a crucial regulator of eye and central nervous system development. Both the spatiotemporal patterns and the precise levels of Pax6 expression are subject to tight control, mediated by an extensive set of cis-regulatory elements. Previous studies have shown that a YAC reporter transgene containing 420Kb of genomic DNA spanning the human PAX6 locus drives expression of a tau-tagged GFP reporter in mice in a pattern that closely resembles that of endogenous Pax6. Here we have closely compared the pattern of tau-GFP reporter expression at the cellular level in the forebrains and eyes of transgenic mice carrying either complete or truncated versions of the YAC reporter transgene with endogenous Pax6 expression and found several areas where expression of tau-GFP and Pax6 diverge. Some discrepancies are due to differences between the intracellular localization or perdurance of tau-GFP and Pax6 proteins, while others are likely to be a consequence of transcriptional differences. We show that cis-regulatory elements that lie outside the 420kb fragment of PAX6 are required for correct expression around the pallial-subpallial boundary, in the amygdala and the prethalamus. Further, we found that the YAC reporter transgene effectively labels cells that contribute to the lateral cortical stream, including cells that arise from the pallium and subpallium, and therefore represents a useful tool for studying lateral cortical stream migration.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Genomic Regions Regulating Pax6 Expression in Embryonic Forebrain Using YAC Reporter Transgenic Mouse Lines

Huang

Kleinjan

et al. 2013

PLoS ONE

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Sox2 and Pax6 maintain the proliferative and developmental potential of gliogenic neural stem cells In vitro

Goméz-López

Wiskow

Favaro

et al. 2011

Glia

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Radial-glia-like neural stem (NS) cells may be derived from neural tissues or via differentiation of pluripotent embryonic stem (ES) cells. However, the mechanisms controlling NS cell propagation and differentiation are not yet fully understood. Here we investigated the roles of Sox2 and Pax6, transcription factors widely expressed in central nervous system (CNS) progenitors, in mouse NS cells. Conditional deletion of either Sox2 or Pax6 in forebrain-derived NS cells reduced their clonogenicity in a gene dosage-dependent manner. Cells heterozygous for either gene displayed moderate proliferative defects, which may relate to human pathologies attributed to SOX2 or PAX6 deficiencies. In the complete absence of Sox2, cells exited the cell cycle with concomitant downregulation of neural progenitor markers Nestin and Blbp. This occurred despite expression of the close relative Sox3. Ablation of Pax6 also caused major proliferative defects. However, a subpopulation of cells was able to expand continuously without Pax6. These Pax6-null cells retained progenitor markers but had altered morphology. They exhibited compromised differentiation into astrocytes and oligodendrocytes, highlighting that the role of Pax6 extends beyond neurogenic competence. Overall these findings indicate that Sox2 and Pax6 are both critical for self-renewal of differentiation-competent radial glia-like NS cells.

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Cell-Autonomous Repression of Shh by Transcription Factor Pax6 Regulates Diencephalic Patterning by Controlling the Central Diencephalic Organizer

et al. 2014

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SummaryDuring development, region-specific patterns of regulatory gene expression are controlled by signaling centers that release morphogens providing positional information to surrounding cells. Regulation of signaling centers themselves is therefore critical. The size and the influence of a Shh-producing forebrain organizer, the zona limitans intrathalamica (ZLI), are limited by Pax6. By studying mouse chimeras, we find that Pax6 acts cell autonomously to block Shh expression in cells around the ZLI. Immunoprecipitation and luciferase assays indicate that Pax6 can bind the Shh promoter and repress its function. An analysis of chimeras suggests that many of the regional gene expression pattern defects that occur in Pax6−/− diencephalic cells result from a non-cell-autonomous position-dependent defect of local intercellular signaling. Blocking Shh signaling in Pax6−/− mutants reverses major diencephalic patterning defects. We conclude that Pax6’s cell-autonomous repression of Shh expression around the ZLI is critical for many aspects of normal diencephalic patterning.

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Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse

Cited by 30 publications

References 45 publications

Identification of Genomic Regions Regulating Pax6 Expression in Embryonic Forebrain Using YAC Reporter Transgenic Mouse Lines

Identification of Genomic Regions Regulating Pax6 Expression in Embryonic Forebrain Using YAC Reporter Transgenic Mouse Lines

Sox2 and Pax6 maintain the proliferative and developmental potential of gliogenic neural stem cells In vitro

Cell-Autonomous Repression of Shh by Transcription Factor Pax6 Regulates Diencephalic Patterning by Controlling the Central Diencephalic Organizer

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