David Greenstein
Office Address

420 Washington Avenue SE
Minneapolis, MN 55455
United States


Greenstein, Ph.D.

Genetics, Cell Biology and Development

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Research interests

Meiosis and fertilization are fundamental and fascinating developmental events, yet they remain incompletely understood despite a century of study. In most sexually reproducing animals, oocytes arrest in meiotic prophase and resume meiosis (meiotic maturation) in response to sperm or somatic cell signals. Proper chromosome segregation during meiosis is critical for the viability of the fertilized egg. In humans, dysregulation of the meiotic process is a major cause of miscarriage, infertility, and Down Syndrome. In many species, hormones trigger signal transduction cascades that regulate meiosis and promote oocyte meiotic maturation and ovulation. Short-range contact-dependent signals between oocytes and somatic cells of the gonad also regulate meiotic maturation. Hormonal dysfunction in humans may play a role in the etiology of meiotic defects because their frequency is increased in both pregnancies of women over forty and early adolescent pregnancies.

To complement studies in vertebrates, the Greenstein lab is using the nematode Caenorhaditis elegans as a model for studying the control of meiosis by intercellular signaling. Sexual reproduction relies on reciprocal soma-germline interactions, in addition to complex interactions between gametes. Our studies demonstrate that the C. elegans major sperm protein (MSP), a cytoskeletal protein required for amoeboid motility of nematode sperm, has a second critical function as a hormone that promotes oocyte meiotic maturation, ovulation, and fertilization. The MSP signal acts on both oocytes and the somatic gonad, culminating in the activation of conserved signaling cascades that promote M-phase entry, cytoskeletal reorganization, meiotic spindle assembly, and fertilization. Ongoing research is aimed at elucidating the molecular mechanisms underlying these key developmental events using a combination of molecular genetics, genomics, biochemistry, and cell biology.

Selected publications

Tolkin, T., Mohammed, A., Starich, T., Schedl, T., Hubbard, E. J. A., & Greenstein, D. (2022). Innexin function dictates the spatial relationship between distal somatic cells in the Caenorhabditis elegans gonad without impacting the germline stem cell pool. eLife 11: e74955.

Spike, C. A., Tsukamoto, T., & Greenstein, D. (2022). Ubiquitin ligases and a processive proteasome facilitate protein clearance during the oocyte-to-embryo transition in Caenorhabditis elegansGenetics 221: iyac051.

Das, D., Seemann, J., Greenstein, D., Schedl, T., & Arur, S. (2022). Reevaluation of the role of LIP-1 as an ERK/MPK-1 dual specificity phosphatase in the C. elegans germline. Proc. Natl. Acad. Sci. USA 119: e2113649119.

Tsukamoto, T, Gearhart, M. D., Kim, S., Mekonnen, G., Spike, C. A., & Greenstein, D. (2020). Insights into the involvement of spliceosomal mutations in myelodysplastic disorders from analysis of SACY-1/DDX41 in Caenorhabditis elegans. Genetics 214: 869–893.

Starich, T. A., Bai, X., & Greenstein, D. (2020). Gap junctions deliver malonyl-CoA from soma to germline to support embryogenesis in Caenorhabditis elegans. Elife 9: e58619.

Spike CA, Huelgas-Morales G, Tsukamoto T, Greenstein D. Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein To Ensure a Robust Oocyte-to-Embryo Transition in Caenorhabditis elegans. Genetics. 2018 Nov;210(3):1011-1037. doi:10.1534/genetics.118.301421. Epub 2018 Sep 11. PubMed PMID: 30206186; PubMed Central PMCID: PMC6218228.

Huelgas Morales G, Greenstein D. C. elegans germline cell death, live! PLoS Genet. 2018 Jul 19;14(7):e1007425. doi: 10.1371/journal.pgen.1007425. eCollection 2018 Jul. PubMed PMID: 30024884; PubMed Central PMCID: PMC6053124.

Huelgas-Morales G, Greenstein D. Control of oocyte meiotic maturation in C. elegans. Semin Cell Dev Biol. 2017 Dec 26. pii: S1084-9521(17)30051-4. doi: 10.1016/j.semcdb.2017.12.005. [Epub ahead of print] Review. PubMed PMID: 29242146; PubMed Central PMCID: PMC6019635.

Tsukamoto, T., Gearhart, M. D., Spike, C. A., Huelgas-Morales, G., Mews, M., Boag, P. R., Beilharz, T. H., & Greenstein, D. (2017). LIN-41 and OMA ribonucleoprotein complexes mediate a translational repression-to-activation switch controlling oocyte meiotic maturation and the oocyte-to-embryo transition in Caenorhabditis elegans. Genetics 206: 1–33. PMCID PMC5560804

Huelgas-Morales, G., Silva-Garcia, C. G., Salinas, L. S., Greenstein, D., & Navarro, R. E. (2016). The stress granule RNA-binding protein TIAR-1 protects female germ cells from heat shock in Caenorhabditis elegans. G3 6: 1031–1047 (with cover).

The TRIM-NHL protein LIN-41 and the OMA RNA-binding proteins antagonistically control the prophase-to-metaphase transition and growth of Caenorhabditis elegans oocytes. Spike CA, Coetzee D, Eichten C, Wang X, Hansen D, Greenstein D. Genetics. 2014 Dec;198(4):1535-58. doi: 10.1534/genetics.114.168831. Epub 2014 Sep 26.

Translational control of the oogenic program by components of OMA ribonucleoprotein particles in Caenorhabditis elegans. Spike CA, Coetzee D, Nishi Y, Guven-Ozkan T, Oldenbroek M, Yamamoto I, Lin R, Greenstein D. Genetics. 2014 Dec;198(4):1513-33. doi: 10.1534/genetics.114.168823. Epub 2014 Sep 26.

Two classes of gap junction channels mediate soma-germline interactions essential for germline proliferation and gametogenesis in Caenorhabditis elegans. Starich TA, Hall DH, Greenstein D. Genetics. 2014 Nov;198(3):1127-53. doi: 10.1534/genetics.114.168815. Epub 2014 Sep 6.

Regulation of maternal Wnt mRNA translation in C. elegans embryos. Oldenbroek M, Robertson SM, Guven-Ozkan T, Spike C, Greenstein D, Lin R. Development. 2013 Nov;140(22):4614-23. doi: 10.1242/dev.096313. Epub 2013 Oct 16.

Kim, S., Spike, C., & Greenstein D. (2013). “Control of oocyte growth and meiotic maturation in C. elegans.” C. elegans germline development (T. Schedl, ed.), in: Advances in experimental medicine and biology (Springer, New York) 757: 277-320.

Ernstrom, G. G., Weimer R., Pawar, D. R., Watanabe, S., Hobson, R. J., Greenstein, D., & Jorgensen, E. M. (2012). “V-ATPase V1 sector is required for corpse clearance and neurotransmission in Caenorhabditis elegans.” Genetics 191: 461-475.

Kim, S., Govindan, J. A., Tu, Z. J., & Greenstein, D. (2012). “The SACY-1 DEAD-box helicase links the somatic control of oocyte meiotic maturation to the sperm-to-oocyte switch and gamete maintenance in Caenorhabditis elegans.” Genetics in press.

Nadarajan, S., Govindan, J. A., McGovern, M., Hubbard, E. J., & Greenstein, D. (2009).“MSP and GLP-1/Notch signaling coordinately regulate actomyosine-dependent cytoplasmic streaming and oocyte growth in C. elegans.” Development 136: 2223-2234.

Govindan, J. A., Nadarajan, S., Kim, S., Starich, T. A., & Greenstein, D. (2009). “Somatic cAMP signaling regulates MSP-dependent oocyte growth and meiotic maturation in C. elegans.” Development 136: 2211-2221.

Cheng, H., Govindan, J. A., & Greenstein, D. (2008). "Regulated trafficking of the MSP/Eph receptor during oocyte meiotic maturation in C. elegans." Current Biology, *18*, 705-714.

Harris, J. E., Govindan, J. A., Yamamoto, I., Schwartz, J., Kaverina, I., & Greenstein, D. (2006). “The major sperm protein signals the reorganization of oocyte microtubles prior to fertilization in Caenorhabditis elegans.” Developmental Biology, 299, 105-121.

Govindan, J. A., Cheng, H., Harris, J. E., & Greenstein, D. (2006). “Gao/i and Gas signaling function in parallel with the MSP/Eph receptor to control meiotic diapause in C. elegans. Current Biology 16, 1257-1268.