Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain

Geena Skariah, Joseph Seimetz, Miles Norsworthy, Monica C. Lannom, Phillip J. Kenny, Mohamed Elrakhawy, Craig Forsthoefel, Jenny Drnevich, Auinash Kalsotra, Stephanie Ceman

Research output: Contribution to journalArticle

Abstract

Background: Moloney leukemia virus 10 (Mov10) is an RNA helicase that mediates access of the RNA-induced silencing complex to messenger RNAs (mRNAs). Until now, its role as an RNA helicase and as a regulator of retrotransposons has been characterized exclusively in cell lines. We investigated the role of Mov10 in the mouse brain by examining its expression over development and attempting to create a Mov10 knockout mouse. Loss of both Mov10 copies led to early embryonic lethality. Results: Mov10 was significantly elevated in postnatal murine brain, where it bound retroelement RNAs and mRNAs. Mov10 suppressed retroelements in the nucleus by directly inhibiting complementary DNA synthesis, while cytosolic Mov10 regulated cytoskeletal mRNAs to influence neurite outgrowth. We verified this important function by observing reduced dendritic arborization in hippocampal neurons from the Mov10 heterozygote mouse and shortened neurites in the Mov10 knockout Neuro2A cells. Knockdown of Fmrp also resulted in shortened neurites. Mov10, Fmrp, and Ago2 bound a common set of mRNAs in the brain. Reduced Mov10 in murine brain resulted in anxiety and increased activity in a novel environment, supporting its important role in the development of normal brain circuitry. Conclusions: Mov10 is essential for normal neuronal development and brain function. Mov10 preferentially binds RNAs involved in actin binding, neuronal projection, and cytoskeleton. This is a completely new and critically important function for Mov10 in neuronal development and establishes a precedent for Mov10 being an important candidate in neurological disorders that have underlying cytoarchitectural causes like autism and Alzheimer's disease.

Original languageEnglish (US)
Article number54
JournalBMC biology
Volume15
Issue number1
DOIs
StatePublished - Jun 29 2017

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Moloney murine leukemia virus
Retroelements
retrotransposons
leukemia
Viruses
brain
Brain
virus
viruses
RNA
messenger RNA
neurites
RNA helicases
RNA Helicases
mice
Messenger RNA
leukaemia
Neurites
RNA-Induced Silencing Complex
complementary DNA

Keywords

  • Brain
  • Embryonic development
  • L1
  • Mov10
  • Neurite outgrowth
  • Neurogenesis
  • RISC
  • RNA helicase
  • Retrotransposons

ASJC Scopus subject areas

  • Biotechnology
  • Structural Biology
  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Plant Science
  • Developmental Biology
  • Cell Biology

Cite this

Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. / Skariah, Geena; Seimetz, Joseph; Norsworthy, Miles; Lannom, Monica C.; Kenny, Phillip J.; Elrakhawy, Mohamed; Forsthoefel, Craig; Drnevich, Jenny; Kalsotra, Auinash; Ceman, Stephanie.

In: BMC biology, Vol. 15, No. 1, 54, 29.06.2017.

Research output: Contribution to journalArticle

Skariah, G, Seimetz, J, Norsworthy, M, Lannom, MC, Kenny, PJ, Elrakhawy, M, Forsthoefel, C, Drnevich, J, Kalsotra, A & Ceman, S 2017, 'Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain', BMC biology, vol. 15, no. 1, 54. https://doi.org/10.1186/s12915-017-0387-1
Skariah G, Seimetz J, Norsworthy M, Lannom MC, Kenny PJ, Elrakhawy M et al. Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. BMC biology. 2017 Jun 29;15(1). 54. https://doi.org/10.1186/s12915-017-0387-1
Skariah, Geena ; Seimetz, Joseph ; Norsworthy, Miles ; Lannom, Monica C. ; Kenny, Phillip J. ; Elrakhawy, Mohamed ; Forsthoefel, Craig ; Drnevich, Jenny ; Kalsotra, Auinash ; Ceman, Stephanie. / Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. In: BMC biology. 2017 ; Vol. 15, No. 1.
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abstract = "Background: Moloney leukemia virus 10 (Mov10) is an RNA helicase that mediates access of the RNA-induced silencing complex to messenger RNAs (mRNAs). Until now, its role as an RNA helicase and as a regulator of retrotransposons has been characterized exclusively in cell lines. We investigated the role of Mov10 in the mouse brain by examining its expression over development and attempting to create a Mov10 knockout mouse. Loss of both Mov10 copies led to early embryonic lethality. Results: Mov10 was significantly elevated in postnatal murine brain, where it bound retroelement RNAs and mRNAs. Mov10 suppressed retroelements in the nucleus by directly inhibiting complementary DNA synthesis, while cytosolic Mov10 regulated cytoskeletal mRNAs to influence neurite outgrowth. We verified this important function by observing reduced dendritic arborization in hippocampal neurons from the Mov10 heterozygote mouse and shortened neurites in the Mov10 knockout Neuro2A cells. Knockdown of Fmrp also resulted in shortened neurites. Mov10, Fmrp, and Ago2 bound a common set of mRNAs in the brain. Reduced Mov10 in murine brain resulted in anxiety and increased activity in a novel environment, supporting its important role in the development of normal brain circuitry. Conclusions: Mov10 is essential for normal neuronal development and brain function. Mov10 preferentially binds RNAs involved in actin binding, neuronal projection, and cytoskeleton. This is a completely new and critically important function for Mov10 in neuronal development and establishes a precedent for Mov10 being an important candidate in neurological disorders that have underlying cytoarchitectural causes like autism and Alzheimer's disease.",
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AU - Elrakhawy, Mohamed

AU - Forsthoefel, Craig

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AB - Background: Moloney leukemia virus 10 (Mov10) is an RNA helicase that mediates access of the RNA-induced silencing complex to messenger RNAs (mRNAs). Until now, its role as an RNA helicase and as a regulator of retrotransposons has been characterized exclusively in cell lines. We investigated the role of Mov10 in the mouse brain by examining its expression over development and attempting to create a Mov10 knockout mouse. Loss of both Mov10 copies led to early embryonic lethality. Results: Mov10 was significantly elevated in postnatal murine brain, where it bound retroelement RNAs and mRNAs. Mov10 suppressed retroelements in the nucleus by directly inhibiting complementary DNA synthesis, while cytosolic Mov10 regulated cytoskeletal mRNAs to influence neurite outgrowth. We verified this important function by observing reduced dendritic arborization in hippocampal neurons from the Mov10 heterozygote mouse and shortened neurites in the Mov10 knockout Neuro2A cells. Knockdown of Fmrp also resulted in shortened neurites. Mov10, Fmrp, and Ago2 bound a common set of mRNAs in the brain. Reduced Mov10 in murine brain resulted in anxiety and increased activity in a novel environment, supporting its important role in the development of normal brain circuitry. Conclusions: Mov10 is essential for normal neuronal development and brain function. Mov10 preferentially binds RNAs involved in actin binding, neuronal projection, and cytoskeleton. This is a completely new and critically important function for Mov10 in neuronal development and establishes a precedent for Mov10 being an important candidate in neurological disorders that have underlying cytoarchitectural causes like autism and Alzheimer's disease.

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