OFCD syndrome and extraembryonic defects are revealed by conditional mutation of the Polycomb-group repressive complex 1.1 (PRC1.1) gene BCOR

Michelle Y. Hamline, Connie M. Corcoran, Joseph A. Wamstad, Isabelle Miletich, Jifan Feng, Jamie L. Lohr, Myriam Hemberger, Paul T. Sharpe, Micah D. Gearhart, Vivian J. Bardwell

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

BCOR is a critical regulator of human development. Heterozygous mutations of BCOR in females cause the X-linked developmental disorder Oculofaciocardiodental syndrome (OFCD), and hemizygous mutations of BCOR in males cause gestational lethality. BCOR associates with Polycomb group proteins to form one subfamily of the diverse Polycomb repressive complex 1 (PRC1) complexes, designated PRC1.1. Currently there is limited understanding of differing developmental roles of the various PRC1 complexes. We therefore generated a conditional exon 9–10 knockout Bcor allele and a transgenic conditional Bcor expression allele and used these to define multiple roles of Bcor, and by implication PRC1.1, in mouse development. Females heterozygous for Bcor exhibiting mosaic expression due to the X-linkage of the gene showed reduced postnatal viability and had OFCD-like defects. By contrast, Bcor hemizygosity in the entire male embryo resulted in embryonic lethality by E9.5. We further dissected the roles of Bcor, focusing on some of the tissues affected in OFCD through use of cell type specific Cre alleles. Mutation of Bcor in neural crest cells caused cleft palate, shortening of the mandible and tympanic bone, ectopic salivary glands and abnormal tongue musculature. We found that defects in the mandibular region, rather than in the palate itself, led to palatal clefting. Mutation of Bcor in hindlimb progenitor cells of the lateral mesoderm resulted in 2/3 syndactyly. Mutation of Bcor in Isl1-expressing lineages that contribute to the heart caused defects including persistent truncus arteriosus, ventricular septal defect and fetal lethality. Mutation of Bcor in extraembryonic lineages resulted in placental defects and midgestation lethality. Ubiquitous over expression of transgenic Bcor isoform A during development resulted in embryonic defects and midgestation lethality. The defects we have found in Bcor mutants provide insights into the etiology of the OFCD syndrome and how BCOR-containing PRC1 complexes function in development.

Original languageEnglish (US)
Pages (from-to)110-132
Number of pages23
JournalDevelopmental Biology
Volume468
Issue number1-2
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
We thank Yasuhiko Kawakami, Anna Petryk, David Zarkower, Wendy Dean, Michael O’Connor and members of the Bardwell lab for discussion and advice, the Copeland/Jenkins lab for recombineering reagents and Charles Hemenway for a mouse Bcor cDNA clone. We also thank Y. Kawakami, Y. Nakagawa, and J Rossant for in situ probes, M. Lewandoski, S. Evans, E. Olson, R. Harvey, T. Mohun and J. Rossant for mice and L. Gammill and D. Garry for reagents. We thank Colleen Forster and the BLS Histology and IHC Laboratory for some tissue processing and histology advice and assistance. This work was supported by funding from the National Institutes of Health 5R01HD084459 and 5R01CA071540 (VJB), 5F30HL093996 (MYH), 5T32DE007288 (JAW), and 5T32GM008244 (MYH), the American Heart Association 0810194Z (MYH), the University of Minnesota Wetzel Fund (MYH), Graduate School , Minnesota Masonic Charities , and Office of the Vice President for Research (VJB) and the UK Medical Research Council MR-K011421/1 (PTS).

Funding Information:
We thank Yasuhiko Kawakami, Anna Petryk, David Zarkower, Wendy Dean, Michael O'Connor and members of the Bardwell lab for discussion and advice, the Copeland/Jenkins lab for recombineering reagents and Charles Hemenway for a mouse Bcor cDNA clone. We also thank Y. Kawakami, Y. Nakagawa, and J Rossant for in situ probes, M. Lewandoski, S. Evans, E. Olson, R. Harvey, T. Mohun and J. Rossant for mice and L. Gammill and D. Garry for reagents. We thank Colleen Forster and the BLS Histology and IHC Laboratory for some tissue processing and histology advice and assistance. This work was supported by funding from the National Institutes of Health 5R01HD084459 and 5R01CA071540 (VJB), 5F30HL093996 (MYH), 5T32DE007288 (JAW), and 5T32GM008244 (MYH), the American Heart Association 0810194Z (MYH), the University of Minnesota Wetzel Fund (MYH), Graduate School, Minnesota Masonic Charities, and Office of the Vice President for Research (VJB) and the UK Medical Research Council MR-K011421/1 (PTS).

Publisher Copyright:
© 2020 Elsevier Inc.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • Cardiac
  • Craniofacial
  • Oculofaciocardiodental syndrome
  • Placenta
  • Salivary glands
  • X-linked developmental disorder

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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