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

3 Citations (Scopus)

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

Fingerprint

Nerve Degeneration
Motor Neurons
Sarcoma
Drosophila
Mutation
Presynaptic Terminals
Diptera
Genes
Larva
Mammals
Neoplasms
Phosphotransferases
Phenotype
Neurons
Messenger RNA

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

Cite this

Azuma, Y., Tokuda, T., Kushimura, Y., Yamamoto, I., Mizuta, I., Mizuno, T., ... 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

Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS. / Azuma, Yumiko; Tokuda, Takahiko; Kushimura, Yukie; Yamamoto, Itaru; Mizuta, Ikuko; Mizuno, Toshiki; Nakagawa, Masanori; Ueyama, Morio; Nagai, Yoshitaka; Iwasaki, Yasushi; Yoshida, Mari; Pan, Duojia; Yoshida, Hideki; Yamaguchi, Masamitsu.

In: Experimental Cell Research, Vol. 371, No. 2, 15.10.2018, p. 311-321.

Research output: Contribution to journalArticle

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, vol. 371, no. 2, pp. 311-321. https://doi.org/10.1016/j.yexcr.2018.08.001
Azuma, Yumiko ; Tokuda, Takahiko ; Kushimura, Yukie ; Yamamoto, Itaru ; Mizuta, Ikuko ; Mizuno, Toshiki ; Nakagawa, Masanori ; Ueyama, Morio ; Nagai, Yoshitaka ; Iwasaki, Yasushi ; Yoshida, Mari ; Pan, Duojia ; Yoshida, Hideki ; Yamaguchi, Masamitsu. / Hippo, Drosophila MST, is a novel modifier of motor neuron degeneration induced by knockdown of Caz, Drosophila FUS. In: Experimental Cell Research. 2018 ; Vol. 371, No. 2. pp. 311-321.
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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.",
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AU - Azuma, Yumiko

AU - Tokuda, Takahiko

AU - Kushimura, Yukie

AU - Yamamoto, Itaru

AU - Mizuta, Ikuko

AU - Mizuno, Toshiki

AU - Nakagawa, Masanori

AU - Ueyama, Morio

AU - Nagai, Yoshitaka

AU - Iwasaki, Yasushi

AU - Yoshida, Mari

AU - Pan, Duojia

AU - Yoshida, Hideki

AU - Yamaguchi, Masamitsu

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