Pax6 Exerts Regional Control of Cortical Progenitor Proliferation via Direct Repression of Cdk6 and Hypophosphorylation of pRb

Mi, Da; Carr, Catherine B.; Georgala, Petrina A.; Huang, Yu-Ting; Manuel, Martine; Jeanes, Emily C.; Niisato, Emi; Sansom, Stephen N.; Livesey, Frederick J.; Theil, Thomas; Hasenpusch‐Theil, Kerstin; Simpson, T. Ian; Mason, John O.; Price, David J.

doi:10.1016/j.neuron.2013.02.012

Cited by 76 publications

(142 citation statements)

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“…Entering all the known targets for these DE miRNAs into GO using DAVID NCBI web page, the terms cell cycle, cell differentiation, cell migration, and corticogenesis were enriched (FDR<0.05). Among the proven targets of these highly conserved miRNAs are mRNAs that have been associated with area 17 and 18 expansion (Lukaszewicz et al, 2005) such as pax6 (Mi et al, 2013) targeted by mir-450b-5p (Shalom-Feuerstein et al, 2012), p27kip targeted by mir-222-3p (Kim et al, 2009), and cdk4 and ccne2 (cyclin E2) targeted by mir-34c-5p (Toyota et al, 2008). Very few proven targets are known for the primate DE miRNAs not expressed in rodent (Fig 2A-C).…”

Section: Resultsmentioning

confidence: 99%

Novel Primate miRNAs Coevolved with Ancient Target Genes in Germinal Zone-Specific Expression Patterns

Arcila

Betizeau

Cambronne

et al. 2014

Neuron

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Summary Major non primate-primate differences in corticogenesis include the dimensions, precursor lineages and developmental timing of the germinal zones (GZ). microRNAs (miRNAs) of laser dissected GZ compartments and cortical plate (CP) from embryonic E80 macaque visual cortex were deep sequenced. The CP and the GZ including Ventricular Zone (VZ), outer and inner subcompartments of the Outer SubVentricular Zone (OSVZ) in area 17 displayed unique miRNA profiles. miRNAs present in primate, but absent in rodent, contributed disproportionately to the differential expression between GZ sub-regions. Prominent among the validated targets of these miRNAs were cell-cycle and neurogenesis regulators. Co-evolution between the emergent miRNAs and their targets suggested that novel miRNAs became integrated into ancient gene circuitry to exert additional control over proliferation. We conclude that multiple cell-cycle regulatory events contribute to the emergence of primate-specific cortical features, including the OSVZ, generated enlarged supragranular layers, largely responsible for the increased primate cortex computational abilities.

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Section: Resultsmentioning

confidence: 99%

Novel Primate miRNAs Coevolved with Ancient Target Genes in Germinal Zone-Specific Expression Patterns

Arcila

Betizeau

Cambronne

et al. 2014

Neuron

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“…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). Uses an alternate splice site in the 3 coding region, which results in a frameshift compared with variant 1.…”

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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“…In Pax6 -mutant cortices, the length of the cell cycle, especially S phase, is markedly longer than it is in control cortices, and this lengthened cell cycle contributes to the decrease in the size of mutant cortices 44 . Mechanistic studies have shown that PAX6 regulates the G1-to-S phase transition in cortical NPs by repressing the cyclin-dependent kinase 6 (CDK6), cyclin D1 and cyclin D2 signalling pathways 45 . Knockout of the cytoskeleton-associated gene filamin A ( Flna ) causes cell cycle prolongation and a reduction in the number of NPs, resulting in a decrease in cortex size 46 .…”

Section: Molecular Mechanisms Of Cortical Growthmentioning

confidence: 99%

Growth and folding of the mammalian cerebral cortex: from molecules to malformations

2014

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The size and extent of folding of the mammalian cerebral cortex are important factors that influence a species’ cognitive abilities and sensorimotor skills. Studies in various animal models and in humans have provided insight into the mechanisms that regulate cortical growth and folding. Both protein-coding genes and microRNAs control cortical size, and recent progress in characterizing basal progenitor cells and the genes that regulate their proliferation has contributed to our understanding of cortical folding. Neurological disorders linked to disruptions in cortical growth and folding have been associated with novel neurogenetic mechanisms and aberrant signalling pathways, and these findings have changed concepts of brain evolution and may lead to new medical treatments for certain disorders.

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Pax6 Exerts Regional Control of Cortical Progenitor Proliferation via Direct Repression of Cdk6 and Hypophosphorylation of pRb

Cited by 76 publications

References 62 publications

Novel Primate miRNAs Coevolved with Ancient Target Genes in Germinal Zone-Specific Expression Patterns

Novel Primate miRNAs Coevolved with Ancient Target Genes in Germinal Zone-Specific Expression Patterns

Pax genes: regulators of lineage specification and progenitor cell maintenance

Growth and folding of the mammalian cerebral cortex: from molecules to malformations

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