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Nicholas Sokol

Nicholas Sokol

  

Assistant Professor

Ph.D., Yale University, 2001
Postdoctoral Fellow, Dartmouth Medical School, 2001-2008

Program Affiliation: Molecular Biology & Genetics

Research Groups Affiliation: Behavior | Cell Biology | Development |Genetics

Phone: 812/856-6812
Fax: 812/855-6082
Email Nick

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MicroRNA Function in Drosophila

let-7-Cluster transcriptional reporter expression
Figure 1: A let-7-Complex transcriptional reporter is expressed in the nervous system of a newly hatched male fly. The muscle system is shown in purple and the let-7-Complex transcriptional reporter is shown in green. The asterisk indicates the location of the ventral nerve cord.

eye assay
Figure 2: Eye assay used to identify let-7-Complex target genes. Panel A depicts a fly carrying a normal copy of the eye pigmentation gene, white. Panel B depicts a fly carrying a copy of white that has been fused to the 3’UTR of a predicted let-7-Complex target gene. The reduction of eye pigment indicates that the 3’UTR represses gene expression. Panel C depicts a fly carrying the same white gene as in Panel B, except that in some eye cells let-7-Complex has been removed.  The derepression of eye pigmentation confirms that let-7-Complex microRNAs regulate gene expression via the target 3’UTR.

MicroRNAs are a recently discovered class of small RNAs that regulate the expression of target genes. Some microRNAs have been highly conserved across millions of years of animal evolution, suggesting that their regulation of particular target genes plays an essential role in animal development and/or function. Yet, for many of these conserved microRNAs, their relevant gene targets as well as their developmental function are not known. We use the fruitfly Drosophila melanogaster to identify the molecular and cellular roles that evolutionarily conserved microRNAs play in the formation and function of complex organisms.

Our current interest is the function of a single gene, let-7-Complex, which encodes three different and highly conserved microRNAs (mir-100, let-7 and miR-125). Flies in which the let-7-Complex gene has been disrupted proceed through development and emerge as normal looking adults. However, these animals are defective in many adult behaviors (flight, locomotion, fertility, egg-laying, etc). We have found that a let-7-Complex transcriptional reporter is expressed throughout the nervous system during metamorphosis (see Figure 1). Therefore, we hypothesize that let-7-Complex microRNAs function in the profound remodeling of the nervous system that occurs during the larval to adult transition. We are taking the following steps to further characterize the function of the let-7-Complex gene.

  1. Analyze let-7-Complex mutant phenotypes. We are currently applying developmental neurobiology approaches to identify the particular neurons in which let-7-Complex microRNAs are expressed as well as characterize the cellular defects caused by their removal. We ultimately hope to connect particular let-7-Complex neuronal circuits to the behaviors affected but their removal.

  2. Characterize let-7-Complex target genes. Using an assay (see Figure 2) that we developed, we identified three target genes that let-7-Complex microRNAs regulate. We are currently studying where, when and why these three target genes need to be regulated by let-7-Complex microRNAs.

  3. Identify genes that regulate let-7-Complex expression and activity. In the eye assay presented in Figure 2, eye color provides a very clear indicator of let-7-Complex activity. This assay can therefore be used to identify genes that regulate let-7-Complex, which can range from transcription factors that specifically activate let-7-Complex expression to microRNA co-factors that regulate microRNA function more generally. We are conducting large-scale genetic screens to identify such genes.

Representative Publications:
[Search Pubmed]

Sokol NS, Identification, detection, and functional analysis of Drosophila microRNAs. Methods in Molecular Biology (2008) forthcoming.

Sokol NS, Xu P, Jan Y-N, Ambros, V. Drosophila let-7 microRNA is required for remodeling of
the neruomusculature during metamorphosis. Genes Dev 2008; 22: 1591-6.

Featured in:

  • Frasch M. A matter of timing: microRNA-controlled temporal identities in
    worms and flies. Genes Dev 2008; 22: 1572-6.

Sokol NS, Ambros V. Mesodermally expressed Drosophila microRNA-1 is regulated by Twist and is required in muscles during larval growth. Genes and Development (2005) 19: 2343-2354.

Featured in:

  • Nguyen H, Frasch M. MicroRNAs in muscle differentiation: lesson from
    Drosophila and beyond. Curr Opin Gen Dev (2006) 16:533-539. [cover]
  • Taylor, M. Developmental Biology: micromanaging muscle growth.
    Current Biology (2006) 16:R20-R23.
  • Brennecke J, Stark A and Cohen S. Not miR-ly muscular: microRNAs and
    muscle development. Genes Dev (2005) 19:2261-2265.

Sempere LF**, Sokol NS**, Dubrovsky EB**, Berger EM, Ambros V.  Temporal regulation of microRNA expression in Drosophila melanogaster mediated by hormonal signals and broad-Complex gene activity. Developmental Biology (2003) 259:9-18.

** co-first authors.