Zac1 functions through TGFbetaII to negatively regulate cell number in the developing retina
| Autor: | Carol Schuurmans, Sarah McFarlane, Robert Cantrup, Lin Ma, Laurent Journot, Natalia Klenin, Dilek Colak, Magdalena Götz, Annie Varrault |
|---|---|
| Přispěvatelé: | Institute of Maternal and Child Health (IMCH), University of Calgary-Calgary Health Region, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institute of Stem Cell Research (GSF), Forschungszentrum für Umwelt und Gesundheit, Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Madeuf, Angie, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Male
Cell division Tumor suppressor gene Cellular differentiation Down-Regulation Apoptosis Cell Count Cell Cycle Proteins Smad2 Protein Biology lcsh:RC346-429 Retina Amacrine cell 03 medical and health sciences Mice 0302 clinical medicine Developmental Neuroscience Retinal Rod Photoreceptor Cells Transforming Growth Factor beta medicine Animals Genes Tumor Suppressor [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Progenitor cell lcsh:Neurology. Diseases of the nervous system 030304 developmental biology Cell Proliferation Feedback Physiological Mice Knockout Neurons 0303 health sciences Cell growth Tumor Suppressor Proteins Gene Expression Regulation Developmental Cell Differentiation Cell cycle Cell biology Mice Inbred C57BL medicine.anatomical_structure Amacrine Cells Phenotype Mutation Female [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Receptors Transforming Growth Factor beta 030217 neurology & neurosurgery Research Article Transcription Factors |
| Zdroj: | Neural Development Neural Development, BioMed Central, 2007, 2 (1), pp.11. ⟨10.1186/1749-8104-2-11⟩ Neural Dev. 2:11 (2007) Neural Development, Vol 2, Iss 1, p 11 (2007) Neural Development, 2007, 2 (1), pp.11. ⟨10.1186/1749-8104-2-11⟩ |
| ISSN: | 1749-8104 |
| Popis: | Background Organs are programmed to acquire a particular size during development, but the regulatory mechanisms that dictate when dividing progenitor cells should permanently exit the cell cycle and stop producing additional daughter cells are poorly understood. In differentiated tissues, tumor suppressor genes maintain a constant cell number and intact tissue architecture by controlling proliferation, apoptosis and cell dispersal. Here we report a similar role for two tumor suppressor genes, the Zac1 zinc finger transcription factor and that encoding the cytokine TGFβII, in the developing retina. Results Using loss and gain-of-function approaches, we show that Zac1 is an essential negative regulator of retinal size. Zac1 mutants develop hypercellular retinae due to increased progenitor cell proliferation and reduced apoptosis at late developmental stages. Consequently, supernumerary rod photoreceptors and amacrine cells are generated, the latter of which form an ectopic cellular layer, while other retinal cells are present in their normal number and location. Strikingly, Zac1 functions as a direct negative regulator of a rod fate, while acting cell non-autonomously to modulate amacrine cell number. We implicate TGFβII, another tumor suppressor and cytokine, as a Zac1-dependent amacrine cell negative feedback signal. TGFβII and phospho-Smad2/3, its downstream effector, are expressed at reduced levels in Zac1 mutant retinae, and exogenous TGFβII relieves the mutant amacrine cell phenotype. Moreover, treatment of wild-type retinae with a soluble TGFβ inhibitor and TGFβ receptor II (TGFβRII) conditional mutants generate excess amacrine cells, phenocopying the Zac1 mutant phenotype. Conclusion We show here that Zac1 has an essential role in cell number control during retinal development, akin to its role in tumor surveillance in mature tissues. Furthermore, we demonstrate that Zac1 employs a novel cell non-autonomous strategy to regulate amacrine cell number, acting in cooperation with a second tumor suppressor gene, TGFβII, through a negative feedback pathway. This raises the intriguing possibility that tumorigenicity may also be associated with the loss of feedback inhibition in mature tissues. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink