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Title: Brg1 coordinates multiple processes during retinogenesis and is a tumor suppressor in retinoblastoma

Retinal development requires precise temp oral and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. Furthermore, when this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. We explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. In spite of the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [3] ;  [1] ;  [3] ;  [4] ;  [5] ;  [5] ;  [6]
  1. St. Jude's Children's Research Hospital, Memphis, TN (United States). Dept. of Developmental Neurobiology
  2. Tokyo Medical and Dental Univ. (Japan). Center for Brain Integration Research
  3. St. Jude's Research Hospital, Memphis, TN (United States). Dept. of Computational Biology
  4. Univ. of Tennessee, Memphis, TN (United States). Health Science Center
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  6. St. Jude's Children's Research Hospital, Memphis, TN (United States). Dept. of Developmental Neurobiology; Univ. of Tennessee, Memphis, TN (United States). Health Science Center; Howard Hughes Medical Inst., Chevy Chase, MD (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Development (Cambridge)
Additional Journal Information:
Journal Name: Development (Cambridge); Journal Volume: 142; Journal Issue: 23; Journal ID: ISSN 0950-1991
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES SWI/SNF; epigenetics; retina development; retinoblastoma; mouse
OSTI Identifier:
1378673
Alternate Identifier(s):
OSTI ID: 1378673