Modeling Human MEGF10 Myopathy in Drosophila melanogaster.
Matin, Bahar.
2015
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Abstract: MEGF10
myopathy or EMARDD (Early onset of Myopathy, Areflexia, Reparatory Distress and
Dysphagia) is a rare human congenital muscle disease caused by mutations in MEGF10. This
single transmembrane receptor is expressed in skeletal muscles, the retina and in CNS
glial cells, and is conserved through evolution. The Drosophila melanogaster (i.e. fruit
fly) homolog of human MEGF10 is ... read moreDrpr. Conservation of MEGF10 from insect to human,
together with the versatility of fly genetics, makes Drosophila a good model organism to
investigate mechanisms underlying human MEGF10 pathogenesis. In this study, a
loss-of-function mutant Drosophila model of MEGF10 myopathy (which displays muscle
defects reminiscent of those seen in EMARDD patients) was utilized to further clarify
the link between MEGF10/Drpr, and signaling pathways involved in muscle development and
regeneration. To achieve this objective, the expression level of candidate partners of
MEGF10/Drpr that comprise the Notch and Wnt signaling cascades was assessed in Drpr null
flies, (vs. controls). These studies revealed a decrease in the expression levels of arm
and Pi3K68D, the fly orthologs of human β-catenin and Pi3K, respectively, which
are two important effectors in the Wnt pathway. In addition, decreased expression of Dl,
the fly homolog of human Delta and a ligand for Notch, was also observed. In parallel to
the Drpr loss-of-function mutant, MEGF10/Drpr gain-of-function Drosophila models were
generated and characterized in our laboratory. Mutant flies that express mouse Megf10
display increased pre-adult lethality. The rare flies that survive to adulthood showed a
shortened lifespan, reduced motor function and morphological abnormalities in the legs.
These phenotypes are recapitulated in flies that overexpress other members of the MEGF
family of receptors, e.g. each of the three known fly Drpr protein isoforms, or mouse
Megf12. Together our results illustrate the importance of balanced MEGF10/Drpr levels in
vivo to sustain normal muscle physiology and survival. Furthermore, we have begun to
unravel a role for MEGF10/Drpr via its interaction with the Wnt and Notch signaling
pathways, which are major regulators of muscle progenitor cells
proliferation/differentiation. Future studies will help further delineate the signaling
cascades downstream of MEGF10/Drpr. Extending from these investigations, candidate
therapeutic strategies that increase the levels of Wnt and/or Notch signaling may be
considered as treatment options for MEGF10 myopathy. To that extent, our MEGF10/Drpr
mutant Drosophila models of MEG10 myopathy can be utilized as in vivo screening
platforms to expedite the identification of candidate
therapeutics.
Thesis (M.S.)--Tufts University, 2015.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Alan Kopin.
Committee: Isabelle Draper, and Martin Beinborn.
Keyword: Pharmacology.read less - ID:
- x633fc94v
- Component ID:
- tufts:20434
- To Cite:
- TARC Citation Guide EndNote
