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Pten is essential for embryonic development and tumour suppression
A Di Cristofano1, B Pesce, C Cordon-Cardo
1Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, NY 10021, USA.
Abstract:
The PTEN gene encodes a dual-specificity phosphatase mutated in a variety of human cancers. PTEN germline mutations are found in three related human autosomal dominant disorders, Cowden disease (CD), Lhermitte-Duclos disease (LDD) and Bannayan-Zonana syndrome (BZS), characterized by tumour susceptibility and developmental defects. To examine the role of PTEN in ontogenesis and tumour suppression, we disrupted mouse Pten by homologous recombination. Pten inactivation resulted in early embryonic lethality. Pten-/- ES cells formed aberrant embryoid bodies and displayed an altered ability to differentiate into endodermal, ectodermal and mesodermal derivatives. Pten+/- mice and chimaeric mice derived from Pten+/- ES cells showed hyperplastic-dysplastic changes in the prostate, skin and colon, which are characteristic of CD, LDD and BZS. They also spontaneously developed germ cell, gonadostromal, thyroid and colon tumours. In addition, Pten inactivation enhanced the ability of ES cells to generate tumours in nude and syngeneic mice, due to increased anchorage-independent growth and aberrant differentiation. These results support the notion that PTEN haploinsufficiency plays a causal role in CD, LDD and BZS pathogenesis, and demonstrate that Pten is a tumour suppressor essential for embryonic development.
Insights
The PTEN gene is crucial for embryonic development and acts as a tumor suppressor. Its disruption in mice leads to developmental defects and increased tumor formation, supporting its role in human diseases like Cowden syndrome.
Area of Science:
- Molecular Biology
- Developmental Biology
- Oncology
Background:
- The PTEN gene encodes a phosphatase involved in cell growth and tumor suppression.
- Germline PTEN mutations cause autosomal dominant disorders: Cowden disease (CD), Lhermitte-Duclos disease (LDD), and Bannayan-Zonana syndrome (BZS).
Purpose of the Study:
- To investigate the role of PTEN in embryonic development and tumor suppression.
- To model human PTEN-associated disorders in mice.
Main Methods:
- Homologous recombination was used to disrupt the mouse Pten gene.
- Embryonic stem (ES) cells and chimeric mice were generated from Pten-inactivated cells.
- Tumor development and differentiation potential were assessed in vivo and in vitro.
Main Results:
- Complete Pten inactivation (Pten-/-) caused early embryonic lethality.
- Pten deficiency in ES cells impaired differentiation into all three germ layers.
- Pten+/- mice and chimeras exhibited hyperplastic-dysplastic changes and developed spontaneous tumors (germ cell, gonad, thyroid, colon).
- Pten inactivation enhanced tumor formation in immunodeficient mice due to increased anchorage-independent growth.
Conclusions:
- PTEN haploinsufficiency is implicated in the pathogenesis of CD, LDD, and BZS.
- Pten is essential for normal embryonic development and acts as a critical tumor suppressor.