Person:
Dimlich, Douglas

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Dimlich

First Name

Douglas

Name

Dimlich, Douglas
Author's Publications: search.filters.isAuthorOfPublication.e6779842-ee98-4661-8e23-9485409bed52

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication
    Genetic Circuitry of Survival Motor Neuron, the Gene Underlying Spinal Muscular Atrophy
    (Proceedings of the National Academy of Sciences, 2013) Sen, Anindya Kumar; Dimlich, Douglas; Guruharsha, K. G.; Kankel, Mark William; Hori, Kazuya; Yokokura, Takakazu; Brachat, Sophie; Richardson, Delwood; Loureiro, Joseph; Sivasankaran, Rajeev; Curtis, Daniel; Davidow, Lance; Rubin, Lee; Hart, Anne C.; Van Vactor, David; Artavanis-Tsakonas, Spyridon
    The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA.
  • Thumbnail Image
    Publication
    Modeling Spinal Muscular Atrophy in Drosophila
    (Public Library of Science, 2008) Chang, Howard Chia-Hao; Yokokura, Takakazu; Mukherjee, Ashim; Kankel, Mark W.; Sridhar, Vasanthi; Hart, Anne C.; Dimlich, Douglas; Sen, Anindya Kumar; Fulga, Tudor Alexandru; Van Vactor, David; Artavanis-Tsakonas, Spyridon
    Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets.