Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies.
Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pd...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2672303?pdf=render |
| _version_ | 1819198434246131712 |
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| author | Bin Zhang Jufang Chang Ming Fu Jie Huang Rakesh Kashyap Ezequiel Salavaggione Sanjay Jain Shashikant Kulkarni Matthew A Deardorff Maria L Giovannucci Uzielli Dale Dorsett David C Beebe Patrick Y Jay Robert O Heuckeroth Ian Krantz Jeffrey Milbrandt |
| author_facet | Bin Zhang Jufang Chang Ming Fu Jie Huang Rakesh Kashyap Ezequiel Salavaggione Sanjay Jain Shashikant Kulkarni Matthew A Deardorff Maria L Giovannucci Uzielli Dale Dorsett David C Beebe Patrick Y Jay Robert O Heuckeroth Ian Krantz Jeffrey Milbrandt |
| author_sort | Bin Zhang |
| collection | DOAJ |
| description | Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B(-/-) mice. While Pds5A(-/-) and Pds5B(-/-) mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A(-/-) or Pds5B(-/-) mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS. |
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| format | Article |
| id | doaj.art-e2e6fd0691444438ad56718d342b4f0b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T03:00:23Z |
| publishDate | 2009-01-01 |
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| spelling | doaj.art-e2e6fd0691444438ad56718d342b4f0b2022-12-21T18:02:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0145e523210.1371/journal.pone.0005232Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies.Bin ZhangJufang ChangMing FuJie HuangRakesh KashyapEzequiel SalavaggioneSanjay JainShashikant KulkarniMatthew A DeardorffMaria L Giovannucci UzielliDale DorsettDavid C BeebePatrick Y JayRobert O HeuckerothIan KrantzJeffrey MilbrandtCornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B(-/-) mice. While Pds5A(-/-) and Pds5B(-/-) mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A(-/-) or Pds5B(-/-) mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS.http://europepmc.org/articles/PMC2672303?pdf=render |
| spellingShingle | Bin Zhang Jufang Chang Ming Fu Jie Huang Rakesh Kashyap Ezequiel Salavaggione Sanjay Jain Shashikant Kulkarni Matthew A Deardorff Maria L Giovannucci Uzielli Dale Dorsett David C Beebe Patrick Y Jay Robert O Heuckeroth Ian Krantz Jeffrey Milbrandt Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. PLoS ONE |
| title | Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. |
| title_full | Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. |
| title_fullStr | Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. |
| title_full_unstemmed | Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. |
| title_short | Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies. |
| title_sort | dosage effects of cohesin regulatory factor pds5 on mammalian development implications for cohesinopathies |
| url | http://europepmc.org/articles/PMC2672303?pdf=render |
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