Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS

Yumiko Azuma, Takahiko Tokuda, Yukie Kushimura, Itaru Yamamoto, Ikuko Mizuta, Toshiki Mizuno, Masanori Nakagawa, Morio Ueyama, Yoshitaka Nagai, Yasushi Iwasaki, Mari Yoshida, Duojia Pan, Hideki Yoshida, Masamitsu Yamaguchi

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Mutations in the Fused in Sarcoma (FUS) gene have been identified in familial ALS in human. Drosophila contains a single ortholog of human FUS called Cabeza (Caz). We previously established Drosophila models of ALS targeted to Caz, which developed the locomotive dysfunction and caused anatomical defects in presynaptic terminals of motoneurons. Accumulating evidence suggests that ALS and cancer share defects in many cellular processes. The Hippo pathway was originally discovered in Drosophila and plays a role as a tumor suppressor in mammals. We aimed to determine whether Hippo pathway genes modify the ALS phenotype using Caz knockdown flies. We found a genetic link between Caz and Hippo (hpo), the Drosophila ortholog of human Mammalian sterile 20-like kinase (MST) 1 and 2. Loss-of-function mutations of hpo rescued Caz knockdown-induced eye- and neuron-specific defects. The decreased Caz levels in nuclei induced by Caz knockdown were also rescued by loss of function mutations of hpo. Moreover, hpo mRNA level was dramatically increased in Caz knockdown larvae, indicating that Caz negatively regulated hpo. Our results demonstrate that hpo, Drosophila MST, is a novel modifier of Drosophila FUS. Therapeutic targets that inhibit the function of MST could modify the pathogenic processes of ALS.

Original languageEnglish (US)
Pages (from-to)311-321
Number of pages11
JournalExperimental Cell Research
Volume371
Issue number2
DOIs
StatePublished - Oct 15 2018

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Cabeza (Caz)
  • Drosophila
  • Fused in Sarcoma (FUS)
  • Hippo (hpo)
  • Mammalian sterile 20 (STE20)-kinase (MST)

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Azuma, Y., Tokuda, T., Kushimura, Y., Yamamoto, I., Mizuta, I., Mizuno, T., Nakagawa, M., Ueyama, M., Nagai, Y., Iwasaki, Y., Yoshida, M., Pan, D., Yoshida, H., & Yamaguchi, M. (2018). Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS. Experimental Cell Research, 371(2), 311-321. https://doi.org/10.1016/j.yexcr.2018.08.001