Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization

Martine Manuel, Petrina A. Georgala, Catherine B. Carr, Simon Chanas, Dirk A. Kleinjan, Ben Martynoga, John O. Mason, Michael Molinek, Jeni Pinson, Thomas Pratt, Jane C. Quinn, T. Ian Simpson, David A. Tyas, Veronica van Heyningen, John D. West, David J. Price

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Abstract

Levels of expression of the transcription factor Pax6 vary throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow radient across the cortical proliferative zone. Previous loss-of-function studies have indicated that Pax6 is required for normal cortical progenitor proliferation, neuronal differentiation, cortical lamination and cortical arealization, but whether and how its level of expression affects its function is unclear. We studied the developing cortex of PAX77 YAC transgenic mice carrying several copies of the human PAX6 locus with its full complement of regulatory regions. We found that PAX77 embryos express Pax6 in a normal spatial pattern, with levels up to three times higher than wild type. By crossing PAX77 mice with a new YAC transgenic line that reports Pax6 expression (DTy54), we showed that increased expression is limited by negative autoregulation. Increased expression reduces proliferation of late cortical progenitors specifically, and analysis of PAX77'wild-type chimeras indicates that the defect is cell autonomous. We analyzed cortical arealization in PAX77 mice and found that, whereas the loss of Pax6 shifts caudal cortical areas rostrally, Pax6 overexpression at levels predicted to shift rostral areas caudally has very little effect. These findings indicate that Pax6 levels are stabilized by autoregulation, that the proliferation of cortical progenitors is sensitive to altered Pax6 levels and that cortical arealization is not.
Original languageEnglish
Pages (from-to)545-555
Number of pages11
JournalDevelopment (Cambridge)
Volume134
Issue number3
DOIs
Publication statusPublished - 2007

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Homeostasis
Nucleic Acid Regulatory Sequences
Transgenic Mice
Transcription Factors
Embryonic Structures

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Manuel, Martine ; Georgala, Petrina A. ; Carr, Catherine B. ; Chanas, Simon ; Kleinjan, Dirk A. ; Martynoga, Ben ; Mason, John O. ; Molinek, Michael ; Pinson, Jeni ; Pratt, Thomas ; Quinn, Jane C. ; Simpson, T. Ian ; Tyas, David A. ; van Heyningen, Veronica ; West, John D. ; Price, David J. / Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization. In: Development (Cambridge). 2007 ; Vol. 134, No. 3. pp. 545-555.
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title = "Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization",
abstract = "Levels of expression of the transcription factor Pax6 vary throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow radient across the cortical proliferative zone. Previous loss-of-function studies have indicated that Pax6 is required for normal cortical progenitor proliferation, neuronal differentiation, cortical lamination and cortical arealization, but whether and how its level of expression affects its function is unclear. We studied the developing cortex of PAX77 YAC transgenic mice carrying several copies of the human PAX6 locus with its full complement of regulatory regions. We found that PAX77 embryos express Pax6 in a normal spatial pattern, with levels up to three times higher than wild type. By crossing PAX77 mice with a new YAC transgenic line that reports Pax6 expression (DTy54), we showed that increased expression is limited by negative autoregulation. Increased expression reduces proliferation of late cortical progenitors specifically, and analysis of PAX77'wild-type chimeras indicates that the defect is cell autonomous. We analyzed cortical arealization in PAX77 mice and found that, whereas the loss of Pax6 shifts caudal cortical areas rostrally, Pax6 overexpression at levels predicted to shift rostral areas caudally has very little effect. These findings indicate that Pax6 levels are stabilized by autoregulation, that the proliferation of cortical progenitors is sensitive to altered Pax6 levels and that cortical arealization is not.",
keywords = "Open access version available, Autoregulation, Chimeras, Cortex, Lamination, Neurogenesis, Overexpression, Pax6, Proliferation, Regionalization, Thalamocortical",
author = "Martine Manuel and Georgala, {Petrina A.} and Carr, {Catherine B.} and Simon Chanas and Kleinjan, {Dirk A.} and Ben Martynoga and Mason, {John O.} and Michael Molinek and Jeni Pinson and Thomas Pratt and Quinn, {Jane C.} and Simpson, {T. Ian} and Tyas, {David A.} and {van Heyningen}, Veronica and West, {John D.} and Price, {David J.}",
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year = "2007",
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Manuel, M, Georgala, PA, Carr, CB, Chanas, S, Kleinjan, DA, Martynoga, B, Mason, JO, Molinek, M, Pinson, J, Pratt, T, Quinn, JC, Simpson, TI, Tyas, DA, van Heyningen, V, West, JD & Price, DJ 2007, 'Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization', Development (Cambridge), vol. 134, no. 3, pp. 545-555. https://doi.org/10.1242/dev.02764

Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization. / Manuel, Martine; Georgala, Petrina A.; Carr, Catherine B.; Chanas, Simon; Kleinjan, Dirk A.; Martynoga, Ben; Mason, John O.; Molinek, Michael; Pinson, Jeni; Pratt, Thomas; Quinn, Jane C.; Simpson, T. Ian; Tyas, David A.; van Heyningen, Veronica; West, John D.; Price, David J.

In: Development (Cambridge), Vol. 134, No. 3, 2007, p. 545-555.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization

AU - Manuel, Martine

AU - Georgala, Petrina A.

AU - Carr, Catherine B.

AU - Chanas, Simon

AU - Kleinjan, Dirk A.

AU - Martynoga, Ben

AU - Mason, John O.

AU - Molinek, Michael

AU - Pinson, Jeni

AU - Pratt, Thomas

AU - Quinn, Jane C.

AU - Simpson, T. Ian

AU - Tyas, David A.

AU - van Heyningen, Veronica

AU - West, John D.

AU - Price, David J.

N1 - Imported on 12 Apr 2017 - DigiTool details were: Journal title (773t) = Development (Cambridge). ISSNs: 0950-1991;

PY - 2007

Y1 - 2007

N2 - Levels of expression of the transcription factor Pax6 vary throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow radient across the cortical proliferative zone. Previous loss-of-function studies have indicated that Pax6 is required for normal cortical progenitor proliferation, neuronal differentiation, cortical lamination and cortical arealization, but whether and how its level of expression affects its function is unclear. We studied the developing cortex of PAX77 YAC transgenic mice carrying several copies of the human PAX6 locus with its full complement of regulatory regions. We found that PAX77 embryos express Pax6 in a normal spatial pattern, with levels up to three times higher than wild type. By crossing PAX77 mice with a new YAC transgenic line that reports Pax6 expression (DTy54), we showed that increased expression is limited by negative autoregulation. Increased expression reduces proliferation of late cortical progenitors specifically, and analysis of PAX77'wild-type chimeras indicates that the defect is cell autonomous. We analyzed cortical arealization in PAX77 mice and found that, whereas the loss of Pax6 shifts caudal cortical areas rostrally, Pax6 overexpression at levels predicted to shift rostral areas caudally has very little effect. These findings indicate that Pax6 levels are stabilized by autoregulation, that the proliferation of cortical progenitors is sensitive to altered Pax6 levels and that cortical arealization is not.

AB - Levels of expression of the transcription factor Pax6 vary throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow radient across the cortical proliferative zone. Previous loss-of-function studies have indicated that Pax6 is required for normal cortical progenitor proliferation, neuronal differentiation, cortical lamination and cortical arealization, but whether and how its level of expression affects its function is unclear. We studied the developing cortex of PAX77 YAC transgenic mice carrying several copies of the human PAX6 locus with its full complement of regulatory regions. We found that PAX77 embryos express Pax6 in a normal spatial pattern, with levels up to three times higher than wild type. By crossing PAX77 mice with a new YAC transgenic line that reports Pax6 expression (DTy54), we showed that increased expression is limited by negative autoregulation. Increased expression reduces proliferation of late cortical progenitors specifically, and analysis of PAX77'wild-type chimeras indicates that the defect is cell autonomous. We analyzed cortical arealization in PAX77 mice and found that, whereas the loss of Pax6 shifts caudal cortical areas rostrally, Pax6 overexpression at levels predicted to shift rostral areas caudally has very little effect. These findings indicate that Pax6 levels are stabilized by autoregulation, that the proliferation of cortical progenitors is sensitive to altered Pax6 levels and that cortical arealization is not.

KW - Open access version available

KW - Autoregulation

KW - Chimeras

KW - Cortex

KW - Lamination

KW - Neurogenesis

KW - Overexpression

KW - Pax6

KW - Proliferation

KW - Regionalization

KW - Thalamocortical

U2 - 10.1242/dev.02764

DO - 10.1242/dev.02764

M3 - Article

VL - 134

SP - 545

EP - 555

JO - Development

JF - Development

SN - 0950-1991

IS - 3

ER -