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Published on: September 8, 2021
Functional analysis of the tumour suppressor gene PTEN in murine B cells and keratinocytes
1Department of Molecular Biology, Akita University School of Medicine, Hondo 1-1-1, Akita 010-8543, Japan. suzuki@med.akita-u.ac.jp
Abstract:
To investigate the roles of the PTEN (phosphatase and tensin homologue deleted from chromosome 10)/PI3K (phosphoinositide 3-kinase) signalling pathway in vivo, we have generated a series of mutant mice with null or tissue-specific gene-targeted deletions of Pten. Here we present our investigations of Pten function in B cells and keratinocytes in mice. Mice with a B cell-specific mutation of Pten showed increased serum autoantibodies and elevated numbers of B1a cells. Among conventional B (B2) cells in mutant spleens, numbers of marginal zone B cells were significantly increased, while those of follicular B cells were reciprocally decreased. Immunoglobulin class switch recombination was defective and associated with impaired induction of activation-induced cytidine deaminase. Mice with a keratinocyte-specific mutation of Pten exhibited epidermal hyperplasia, hyperkeratosis and accelerated skin morphogenesis. Within 3 weeks of birth, 90% of these animals died of malnutrition, possibly caused by hyperkeratosis of the oesophageal epithelia. Surviving mutant mice developed spontaneous skin tumours within 8.5 months of birth, and chemical treatment accelerated the onset of tumours. Our data show that PTEN is an important regulator in B cells and keratinocytes.
Insights
The phosphatase and tensin homologue deleted from chromosome 10 (PTEN) protein is crucial for regulating B cells and skin cells. PTEN mutations in mice led to autoimmune diseases and skin abnormalities, highlighting its regulatory roles.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- The PTEN/PI3K signaling pathway is vital in cellular functions.
- Dysregulation of PTEN is implicated in various diseases, including cancer and autoimmune disorders.
- Understanding PTEN's in vivo roles requires tissue-specific investigation.
Purpose of the Study:
- To elucidate the in vivo functions of PTEN in B lymphocytes and keratinocytes.
- To investigate the impact of Pten gene deletions on immune cell populations and skin development.
- To determine PTEN's role as a regulator in specific cell types.
Main Methods:
- Generation of mice with null or tissue-specific Pten gene deletions.
- Analysis of B cell populations (B1a, B2, marginal zone, follicular) and serum autoantibodies.
- Histopathological examination of skin and esophageal epithelia, and assessment of tumor development.
Main Results:
- B cell-specific Pten deletion resulted in increased autoantibodies, elevated B1a cells, expanded marginal zone B cells, and reduced follicular B cells.
- Defective immunoglobulin class switch recombination and impaired activation-induced cytidine deaminase induction were observed in mutant B cells.
- Keratinocyte-specific Pten deletion caused epidermal hyperplasia, hyperkeratosis, accelerated skin morphogenesis, and high early mortality due to esophageal issues.
- Mutant mice developed spontaneous skin tumors, with accelerated onset upon chemical induction.
Conclusions:
- PTEN is a critical regulator of B cell homeostasis and function.
- PTEN plays a significant role in keratinocyte proliferation, differentiation, and skin development.
- PTEN's tumor-suppressive function is evident in both immune and epithelial cells.
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