Immunology Graduate Program | University of California, San Francisco

Michael McManus, PhD

Mammalian microRNA and RNA Interference Pathways

Asst. Professor, Department of Microbiology & Immunology, Diabetes Center
513 Parnassus Ave. Box 0534 - HSW Room 1053A
San Francisco, CA 94143

(415) 502-2049 tel
mmcmanus@diabetes.ucsf.edu

Lab website: http://mcmanuslab.ucsf.edu/

Description of Research

The McManus lab studies biological processes relating to RNA interference pathways, using the mouse as a model. This includes the study of small (18-26 nucleotide) regulatory RNAs of biological significance, such as microRNAs, and the genetic factors involved in small RNA genesis.

In the past few years several groups have published the sequences for over 1000 microRNAs from plants to humans and this number is growing. In fact, approximately 1% of all known human genes encode microRNAs, yet we know very little about their function. Our lab is interested in understanding how microRNAs contribute to the specification of cell fate, and how disregulation of microRNAs may contribute to human disease.

We have generated a mouse knockout for the gene called Dicer, which is the catalytic engine of small RNA production in cells. We are using this mouse to explore the role of small RNAs in developmental and immune biology settings. The roles of small RNAs may be much broader than anticipated, thus Dicer may be a 'master regulator' in a number of different contexts. Genetic data in C. elegans indicates that Dicer depletion results in loss of the ability to do RNA interference and developmental defects. In S. pombe, knockout of Dicer results in loss of heterochromatic silencing, suggesting a potential role for small RNAs in transcriptional gene silencing. In fact, evidence is accumulating that small RNAs may be key mediators in DNA methylation. We believe that the small regulatory RNAs that have discovered are just the 'tip of the iceberg' in a set of important biologies that we are far from understanding.
Current projects include the use of RNA expression arrays (both mRNA and microRNA), mouse transgenics (both knock-outs and knock-ins), and biochemical approaches in cell culture aimed at dissecting mechanisms of small RNA biology.

McManus, MT (2004). Small RNAs in Immunity. Immunity, 21 (6): 2004.

Mansfield, JH, Harfe B, Nissen, R, Obenaur J, Srineel J, Chaudhuri A, Farzan-Kashani R, Zuker M, Pasquinelli AE, Ruvkyun G, Sharp PA, Tabin CJ,
McManus, MT (2004). microRNA-responsive transgenes reveal Hox-like and other developmentally regulated patterns of vertebrate microRNA expression. Nature Genetics, (10):1079-83.

Ventura A, Meissner A, Dillon CP, McManus, MT , Sharp PA, Van Parijs, L, Jaenisch R, Jacks, T (2004). A Cre-lox based method for conditional RNA interference in mice and cells. PNAS, 101(28):10380-10385.

McManus, MT (2003). MicroRNAs in Cancer, Seminars in Cancer Biology, 13:253-258.

Ge Q, McManus, MT , Nguyen T, Sharp PA, Eisen HE, and Chen J. (2003) RNA interference of Influenza virus production by both mRNA-specific and virus-specific mechanisms. PNAS, 100(5):2718-2723.

Rubinson DA, Dillon CP, Kwiatkowski AV, Sievers C, Yang L, Kopinja J, Zhang M, McManus, MT , Gertler FB, Scott ML, Van Parijs L. (2003). A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference, Nature Genetics, 33(3):401-406.

McManus, MT , Haines BB, Dillon C, Whitehurst CE, van Parijs L, Chen J. and Sharp PA (2002). siRNA-mediated gene silencing in T-lymphocytes, J. of Immunology, 169:10, 5754-5760.

McManus, MT and Sharp PA (2002). Gene silencing in mammals by siRNAs, Nature Reviews Genetics,3:10,737-747.

McManus, MT , Petersen, CP, Haines, B, Chen, J. and Sharp PA (2002). Gene Silencing using micro-RNA designed hairpins, RNA, 8:842-850.