Fadya Farid

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The Diverse Functions of MicroRNAs In Animal
Development and Diseases
Fadya Farid
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Outline

• Introduction.
• Functions of miRNAs.
• miRNAs involved in cancer.
• Diseases Associated with changes in the sequence
  of the miRNA or the miRNA Target Site.
• miRNAs Associated with viral infection.

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1. Introduction

• miRNAs are small noncoding RNAs of 22nt that
  influence mRNA stability and translation.
• The first miRNA, lin-4, was identified in 1993
  in a genetic screen for mutants that disrupt the
  timing of post-embryonic development in
  Caenorhabiditis elegans.

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microMaturationIn Animals, two processing steps
yield mature miRNAs.

• Step 1 generation of 70nt pre-miRNAs from
  the longer transcripts (pri-miRNAs)
• Step 2 processing or pre-miRNAs into mature
  miRNAs.

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2. Functions of miRNAs.

• Loss of All miRNAs They all play important
  roles in animal development.
• miRNAs as regulators of developmental Timing.
• miRNAs Involved in Signaling Pathways.
• miRNAs in Apoptosis and Metabolism.
• miRNAs Involved in Myogenesis and Cardiogenesis.
• miRNAs in the Brain.

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• From their conservation and expression patterns,
  its clear that miRNAs play an important role in
  animal development.
• HOW?

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Animal without miRNAs Cannot live or reproduce

• For example
• Mice deficient in dicer die at embryonic day7.5
  and lack multipotent stem cells

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miRNA Lin-4

• Has two important Functions
• 1. Regulation of Developmental Timing
• lin-4 represses the expression of lin-14 which
  encodes a nuclear protein whose concentration
  must be reduced for worms to progress from their
  first larval stage to the second
• 2. Involved in Signaling Pathways
• Affects life span through a major signaling
  pathway.
• Overexpression of lin-4 resulted in a
  prolonged life span, and lin-4 loss-of-function
  mutations caused premature death.

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miRNA-14

• Functions in Apoptosis and Metabolism.
• 1.A cell death suppressor.
• 2.plays a role in fat metabolism.
• Fly miR-14 mutants are obese and have elevated
  levels of triacyglcerides

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miRNAs Involved in Myogenesis and Cardiogenesis

• miR-1 is highly expressed in the muscles of flies
• and the muscles and heart of mice

• Figure 2. Expression of miR-124a and miR-1
• in Zebrafish, Medaka, Mouse, and Fly
• The expression of miR-124a is restricted to
• the brain and the spinal cord in fish and
• mouse or to the ventral nerve cord in the fly.
• The expression of miR-1 is restricted to the
• muscles and the heart in the mouse. The conserved
• sequence and expression of miR-1
• and miR-124a suggests ancient roles in
• muscle and brain development. The fly and
• medaka pictures were generously provided
• by Eric Lai and Brandon Ason, respectively.

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3. miRNAs involved in cancer

• Initial Evidence came from a study on Chronic
  lymphocytic leukemia.
• A region containing miR-15 and miR-16 at
  chromosome 13q14 is deleted in most cases
• miRNAs located in deleted or amplified regions in
  cancer samples have altered expression levels.

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Figure 3. Mechanisms that Link miRNAs to
Disease There are two possible scenarios (1)
either the expression level of the miRNA changes
due to genomic rearrangements or (2) there is a
gain or loss of an miRNA-target interaction due
to a mutation in a 3UTR or a mutation in the
miRNA.
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4. Diseases Associated with changes in the
sequence of the miRNA or the miRNA Target Site

• 1. Kaposis sarcoma-associated herpesvirus (KSHV)
• SNP in the loop of the pre-mRNA results in
  aberrant processing and therefore reduced
  mi-RNA production. (miRNA polymorphism)
• 2. Tourettes syndrome (TS)
• Results from the mutation in the target
  site for miR-189, replacing a GU wobble base
  pair with an AU pairing.
• 3. Exceptional muscularity of Texel sheep.
• Gain of a target site for miR-1 and miR-206
  which are both known to be strongly expressed in
  muscles.

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5. miRNAs Associated with viral infection

• How does a virus use miRNAs to aid infection?
• One of the miRNAs from the SV40 virus induces
  degradation of viral mRNA coding for T-antigens
  thus making viral-infected cells less sensitive
  to cytotoxic T cells

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Conclusions

• Animals cannot live without miRNAs.
• There is a large repertoire of conserved miRNAs.
• mRNAs contain conserved miRNA target sites.
• Most miRNAs are highly abundant and exhibit
  striking tissue-specific expression.
• The role of miRNAs in several disease related
  processes is now well established.

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• Thank You