Amy Pasquinelli
Assistant Professor of Biology, UCSD

e-mail: apasquin@biomail.ucsd.edu
Lab Homepage

    The recent discovery of microRNAs (miRNAs) has revolutionized our understanding of gene control. Genetic studies in the nematode Caenorhabditis elegans (Figure 1)  revealed the first members of what we now recognize as an extensive family of regulatory RNAs that exist in all multicellular organisms.  Already there is evidence that specific miRNAs play key roles in controlling development, stem cell fates and neuronal differentiation, and mutations in human miRNA genes have been linked to oncogenic and disease states.    The Pasquinelli lab couples C. elegans genetics with molecular and biochemical techniques to understand the basic mechanisms of miRNA expression and function and to elucidate the biological roles of specific miRNAs in cellular differentiation programs.

   How is the expression of miRNAs regulated?  MiRNA genes typically encode long primary transcripts (pri-miRNAs) that undergo multiple processing steps to generate the mature ~22 nucleotide miRNA (Figure 2).  Many miRNA genes are expressed at precise times in development and in specific tissues.  To understand how these temporal and spatial expression patterns are achieved, we study the transcriptional and processing events that cooperate to produce specific miRNAs at the right time and in the right place.

 

How do miRNAs regulate gene expression?  The miRNAs regulate specific genes by partially base-pairing to complementary sequences in the messenger RNAs (mRNAs) of protein-coding genes (Figure 2).  The human genome contains over 300 different miRNA genes, each of which may directly regulate hundreds of protein coding genes.  To help elucidate how miRNAs find and regulate targets with limited sequence complementarity, we focus on specific miRNA genes in C. elegans and use molecular and genetic experiments to identify potential targets. We also subject these candidate target genes to bioinformatic analyses to uncover the regulatory motifs.  Regulation by miRNAs can result in degradation or translational repression of the target mRNA (Figure 2), but the molecular mechanisms behind these inhibitory strategies are not well understood.  By studying defined miRNA and target pathways in C. elegans, my lab hopes to help unravel the novel modes of gene regulation guided by miRNAs.

What is the biological function of miRNA regulatory pathways?  Some miRNA genes, like let-7, are essential for normal development (Figure 1).  The let-7 miRNA and its temporally regulated expression pattern are widely conserved across animal phylogeny and misexpression of this miRNA has been linked to cancer in humans.  A goal of our studies on the worm let-7 gene is to understand the broad role let-7 plays in cellular differentiation events across species.

    Bagga S, Bracht J, Hunter S, Massirer K, Holtz J, Eachus R, Pasquinelli AE. (2005). Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell. 122(4):553-63.

    Bracht J, Hunter S, Eachus R, Weeks P, Pasquinelli AE. (2004). Trans-splicing and polyadenylation of let-7 microRNA primary transcripts. RNA. 10:1586-1594.

    Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, Baillie DL, Fire A, Ruvkun G, Mello CC. (2001). Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 106(1):23-34.

    Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, Hayward DC, Ball EE, Degnan B, Muller P, Spring J, Srinivasan A, Fishman M, Finnerty J, Corbo J, Levine M, Leahy P, Davidson E, Ruvkun G. (2000). Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature. 408(6808):86-9.

Reviews
    Massirer K, Pasquinelli AE. (2006). The evolving role of microRNAs in animal gene expression. BioEssays 28:449-452.

    Pasquinelli AE, Hunter S, Bracht J. (2005). MicroRNAs: a developing story. Curr Opin Genet Dev. Apr;15(2):200-5.

    Pasquinelli AE. (2002). MicroRNAs:  Deviants No Longer. Trends in Genetics.  April; 18(4):171-173.

    Pasquinelli AE, Ruvkun G. (2002). The Role of Heterochronic Genes in Development and Evolution. Annu Rev Cell and Dev Biol. 18:495-513.
Amy Pasquinelli received her Ph.D. in Biomolecular Chemistry from the University of Wisconsin-Madison and was a Helen Hay Whitney Postdoctoral Fellow in the Genetics Department at Harvard Medical School.  Since joining the faculty in 2003, she has been named a Keck Distinguished Young Scholar in Medical Research, a Searle Scholar, a V Foundation for Cancer Research Scholar and a Rosalind Franklin Young Investigator.