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Stem cell division is regulated by the microRNA pathway


One of the key characteristics of stem cells is their capacity to divide for long periods of time in an environment where most of the cells are quiescent. Therefore, a critical question in stem cell biology is how stem cells escape cell division stop signals. Here, we report the necessity of the microRNA (miRNA) pathway1,2,3,4 for proper control of germline stem cell (GSC) division in Drosophila melanogaster. Analysis of GSCs mutant for dicer-1 (dcr-1), the double-stranded RNaseIII essential for miRNA biogenesis, revealed a marked reduction in the rate of germline cyst production. These dcr-1 mutant GSCs exhibit normal identity but are defective in cell cycle control. On the basis of cell cycle markers and genetic interactions, we conclude that dcr-1 mutant GSCs are delayed in the G1 to S transition, which is dependent on the cyclin-dependent kinase inhibitor Dacapo, suggesting that miRNAs are required for stem cells to bypass the normal G1/S checkpoint. Hence, the miRNA pathway might be part of a mechanism that makes stem cells insensitive to environmental signals that normally stop the cell cycle at the G1/S transition.

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Figure 1: Loss of Dcr-1 function in GSCs reduces the rate of egg chamber production.
Figure 2: dcr-1 mutant GSCs remain in the stem cell niche and retain stem cell identity.
Figure 3: dcr-1 causes a cell cycle delay in GSCs.
Figure 4: The GSC division defect is dependent on Dap.


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We thank B. Calvi, B. Wakimoto and E. Ward for comments on the manuscript, and the members of the H.R.-B. laboratory for suggestions throughout the course of this study. We also thank E. Kerr for making dacapo constructs; V. Shcherbatyy for creating transgenic lines; B. Akiyashi for UAS-Dap experiments; K. Kim for the dcr-1d102 strain; and M. Lilly, C. Lehner, I. Hariharan, T. Orr-Weaver, D. McKearin, P. ten Dijke, A. Spradling and C.-H. Heldin for flies, antibodies and advice. This work was supported by the Schultz Fellowship for S.D.H., grants from the National Institutes of Health to R.W.C and H. R.-B., and the American Heart Association and the American Cancer Society to H.R.-B.

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Correspondence to H. Ruohola-Baker.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods, additional references, Supplementary Table S1 and Supplementary Figure Legends. (DOC 50 kb)

Supplementary Figure S1

The dcr-1d102 allele yields a phenotype identical to, albeit slightly milder than the dcr-1Q1147X allele. (JPG 309 kb)

Supplementary Figure S2

The dcr1-related reduction in cell division rate and cell cycle delay are germline stem cell-specific. (a-a'') (JPG 455 kb)

Supplementary Figure S3

Analysis of Dacapo expression in GSCs. (JPG 459 kb)

Supplementary Figure S4

Computational prediction of miRNA binding sites in the dap 3' UTR. (DOC 29 kb)

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Hatfield, S., Shcherbata, H., Fischer, K. et al. Stem cell division is regulated by the microRNA pathway. Nature 435, 974–978 (2005).

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