07 Dec 2001

In the last four years, cancer researchers have come to realize that the lipid phosphatase PTEN is perhaps as important a tumor suppressor as its more famous cousin p53. At the same time, other researchers are trying to harness the almost-mythical regenerative promise of neural stem cells even as they still don't fully understand basic stem cell biology. A paper in today's Science joins these two lines of investigation by suggesting that PTEN not only prevents proliferation in mature cells but, similarly, appears to limit proliferation and self-renewal in neural stem cells.

PTEN mutations or inactivation is involved in human gliomas, breast, prostate and other tumors, and germline mutations occur in three rare human syndromes that all have a high incidence of systemic malignancies (Di Cristofano et al. 2000; Marsh et al. 1997). Other data hinted that PTEN also plays a role in neurodevelopment, but conventional knockout mice die before embryonic day 9. Now, Xin Liu, Hong Wu, and colleagues at University of California, Los Angeles, describe mice in whom PTEN is deleted only in CNS stem and progenitor cells after day nine by tying the inactivating transgene to the nestin promoter. The mice survive until shortly after birth.

These animals' brains are twice as large as normal in terms of both weight and cell number-an effect more pronounced than that seen in mice lacking the cell death inhibitor BCL-2 or the cell cycle break p27, the authors write. (Humans with germline PTEN mutation also have enlarged brains.) Moreover, individual cells from the PTEN conditional knockout mice were larger than those from controls, suggesting PTEN regulates cell size as well as cell number in the developing brain. In addition, the laminar pattern of the cortex, hippocampus, and cerebellum was disturbed, an effect perhaps owing to PTEN's role in enabling the cytoskeletal rearrangement necessary for cell migration. (Besides proliferation and migration, PTEN also influences transcription, glucose metabolism, and apoptosis.)

By culturing aggregates of neuronal progenitors, or neurospheres, the scientists found that the PTEN-deficient cells progressed through the cell cycle faster and fewer died by apoptosis than did controls. Their subsequent differentiation into neurons and different types of glia was unaffected, suggesting that PTEN regulates self-renewal and proliferation of neural stem cells, the authors write.

Two other groups report similar results in the December Nature Genetics. Researchers led by Tak Mak at University of Toronto, and an independent team led by Suzanne Baker at St. Jude Children's Research Hosptital in Memphis, Tennessee, describe conditional PTEN knockout mice that survive up to nine weeks and could be a mouse model for the human PTEN-mutation syndrome Lhermitte-Ducloss disease (Backman 2001, Kwon CH 2001).

Transient PTEN inactivation could be an avenue towards harvesting increased numbers of neural progenitors for research, write Josef Penninger at Amgen Research Institute and James Woodgett at University of Toronto in an accompanying Perspectives article. Coaxing these cells to proliferate abundantly remains difficult in practice. The operative term here is "transient," however, since permanent PTEN loss would incline the cells towards forming tumors, the commentators add.—Gabrielle Strobel

 

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Papers

1. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell. 2000 Feb 18;100(4):387-90. PubMed.
2. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May;16(1):64-7. PubMed.
3. Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, Tsao MS, Shannon P, Bolon B, Ivy GO, Mak TW. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 2001 Dec;29(4):396-403. PubMed.
4. Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, Eberhart CG, Burger PC, Baker SJ. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet. 2001 Dec;29(4):404-11. PubMed.