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Sokol
et al.
, 2008; Zhao
et al.
, 2010
). In Drosophila, let-7 regulates the
timing of neuromuscular remodeling events and adult behaviors (
Caygill
and Johnston, 2008; Sokol
et al.
, 2008
). Additional work in Drosophila has
revealed a potential link between disruption of let-7 function and Parkin-
son's disease. The Parkinson's disease related protein LRRK2 antagonizes
the ability of let-7 to repress target genes (
Gehrke
et al.
, 2010
). In particular,
mis-regulation of the let-7 target
dp
results in loss of fly dopaminergic
neurons, exemplifying the importance of let-7 activity in neuronal health.
It is likely that other targets of let-7 that promote cell division, like
dp
, also
become mis-regulated by pathogenic LRRK2, which results in inappropri-
ate activation of cell division programs in postmitotic neurons, leading to
cell death.
5. Conclusions
Despite only about a decade's worth of research, miRNAs have
emerged as key regulators of development. In particular, the let-7 miRNAs
have been found to play pivotal roles in cell differentiation pathways. The
strict conservation of let-7 sequences across animal species suggests an
ancient function in regulating core genes that control cell division pro-
grams. The essential role of let-7 in regulating temporal development in
model organisms relates to the importance of this miRNA in human disease
phenotypes. In some cases, not only the general pathways but also the
targets of let-7 are conserved across phylogeny. The let-7 miRNA has
also been a model for understanding the complex transcriptional and post-
transcriptional mechanisms that control miRNA biogenesis. The past
decade introduced us to miRNAs and the basic steps for their synthesis
and control of target expression. Future challenges include the elucidation
of mechanisms controlling the levels of specific miRNAs, determination of
features that faithfully predict miRNA target recognition in the endogenous
context, and analysis of gene networks under normal and perturbed
miRNA conditions. Given its conserved and essential role in animal devel-
opment, it is likely that let-7 will continue to be a focus for understanding
the complexities of miRNA expression and function.
ACKNOWLEDGMENTS
We thank members of the Pasquinelli lab for critical reading of this chapter. The Pasquinelli
lab is supported by the US National Institutes of Health (GM071654), Keck, Searle, V,
Emerald and Peter Gruber Foundations.
