An Allelic Series at the Paired Box Gene 6 (Pax6) Locus Reveals the Functional Specificity of Pax Genes

Carbe, Christian; Garg, Ankur; Cai, Zhigang; Li, Hongge; Powers, Andrea; Zhang, Xin

doi:10.1074/jbc.m112.436865

Cited by 28 publications

(25 citation statements)

References 54 publications

(52 reference statements)

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“…Moreover, inserting Pax2 , which lacks a homeodomain, in the Pax6 locus resulted in a rescue of forebrain patterning and neurogenesis. This study further strengthened the case for the necessity of a functional “paired-domain” for proper cortical development (Carbe et al, 2013). …”

Section: Pax6: a Master Regulator Of Cortical Developmentsupporting

confidence: 71%

“…A surprising study uncovered that, in the forebrain, in order to regulate cortical development, the coding region of Pax6 could be replaced by that of Pax2 or Pax6(5a) and still rescue cortical phenotypes associated with Pax6 knockout (though eye phenotypes were not rescued in either scenario) (Carbe et al, 2013). When Pax6 ( 5a ) was expressed in lieu of Pax6 , dorsoventral patterning and progenitor proliferation defects were normalised though defects at the ventral boundary persisted.…”

Section: Pax6: a Master Regulator Of Cortical Developmentmentioning

confidence: 99%

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Transcriptional and epigenetic mechanisms of early cortical development: An examination of how Pax6 coordinates cortical development

Ypsilanti

Rubenstein

2015

J of Comparative Neurology

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The development of the cortex is an elaborate process which integrates a plethora of finely tuned molecular processes ranging from carefully regulated gradients of transcription factors, dynamic changes in the chromatin landscape or formation of protein complexes to elicit and regulate transcription. Combined with cellular processes such as cell type specification, proliferation, differentiation and migration, all of these developmental processes result in the establishment of an adult mammalian cortex with its typical lamination and regional patterning. By examining in-depth the role of one transcription factor, Pax6, on the regulation of cortical development, its integration in the regulation of chromatin state and its regulation by cis-regulatory elements, we aim to demonstrate the importance of integrating each level of regulation in our understanding of cortical development.

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Section: Pax6: a Master Regulator Of Cortical Developmentsupporting

confidence: 71%

Section: Pax6: a Master Regulator Of Cortical Developmentmentioning

confidence: 99%

Transcriptional and epigenetic mechanisms of early cortical development: An examination of how Pax6 coordinates cortical development

Ypsilanti

Rubenstein

2015

J of Comparative Neurology

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“…However, it is important to note that overall Pax6 dosage is not the only important factor. In particular, alternative splicing gives rise to full-length PAX6 proteins with very different regulatory functions, and the balance of these isoforms is an essential factor in the functional equation (Carbe et al, 2013;Duncan et al, 2000;Haubst et al, 2004;Mishra et al, 2002;Pinson et al, 2005). 1Gso phenotypic effects will thus not be resolved fully until Pax6 isoform expression can be analyzed fully and quantitatively in specific tissues and cell types throughout development.…”

Section: Discussionmentioning

confidence: 99%

A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye

Elso

Lü

Weisner

et al. 2013

Genesis

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Pax6 encodes a transcription factor with key roles in the development of the pancreas, central nervous system, and eye. Gene expression is orchestrated by several alternative promoters and enhancer elements that are distributed over several hundred kilobases. Here, we describe a reciprocal translocation, called 1Gso, which disrupts the integrity of transcripts arising from the 5'-most promoter, P0, and separates downstream promoters from enhancers active in pancreas and eye. Despite this fact, 1Gso animals exhibit none of the dominant Pax6 phenotypes, and the translocation complements recessive brain and craniofacial phenotypes. However, 1Gso fails to complement Pax6 recessive effects in lacrimal gland, conjunctiva, lens, and pancreas. The 1Gso animals also express a corneal phenotype that is related to but distinct from that expressed by Pax6 null mutants, and an abnormal density and organization of retinal ganglion cell axons; these phenotypes may be related to a modest upregulation of Pax6 expression from downstream promoters that we observed during development. Our investigation maps the activities of Pax6 alternative promoters including a novel one in developing tissues, confirms the phenotypic consequences of upstream enhancer disruption, and limits the likely effects of the P0 transcript null mutation to recessive abnormalities in the pancreas and specific structures of the eye.

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“…Total RNAs were extracted from postnatal day 3 retinal or kidney samples using TRIZOL (#15596, Life Technologies) as instructed by the product manual, and converted to cDNA using the SuperScript III Reverse Transcriptase kit (#18080, Invitrogen) (Carbe et al, 2013). Two sets of primers were designed to detect the isoform-specific expression of PDGFA .…”

Section: Methodsmentioning

confidence: 99%

Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis

Tao

Zhang

2016

Cell Reports

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SUMMARY The basement membrane is crucial for cell polarity, adhesion and motility, but how it is assembled on cell surface remains unclear. Here, we find that ablation of glycosaminoglycan (GAG) side chains of proteoglycans in the neuroretina disrupts the retinal basement membrane, leading to arrested astrocyte migration and reduced angiogenesis. Using genetic deletion and time-lapse imaging, we show that retinal astrocytes require neuronal-derived PDGF as a chemoattractive cue and the retinal basement membrane as a migratory substrate. Genetic ablation of heparan sulfates does not produce the same defects as GAG null mutants. In contrast, enzymatic removal of heparan sulfates and chondroitin sulfates together inhibits de novo laminin network assembly. These results indicate that both heparan and chondroitin sulfate proteoglycans participate in retinal basement membrane assembly, thus promoting astrocyte migration and angiogenesis.

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An Allelic Series at the Paired Box Gene 6 (Pax6) Locus Reveals the Functional Specificity of Pax Genes

Cited by 28 publications

References 54 publications

Transcriptional and epigenetic mechanisms of early cortical development: An examination of how Pax6 coordinates cortical development

Transcriptional and epigenetic mechanisms of early cortical development: An examination of how Pax6 coordinates cortical development

A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye

Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis

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