Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

Neeraj K. Aryal; Vinod Pant; Amanda R. Wasylishen; Jan Parker-Thornburg; Laura Baseler; Adel K. El-Naggar; Bin Liu; Awdhesh Kalia; Guillermina Lozano; Swathi Arur

doi:10.1073/pnas.1814377116

Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

Neeraj K. Aryal, Vinod Pant, Amanda R. Wasylishen, Jan Parker-Thornburg, Laura Baseler, Adel K. El-Naggar, Bin Liu, Awdhesh Kalia, Guillermina Lozano, Swathi Arur

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans. Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1 ^{S1836D/S1836D} mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals.

Original language	English (US)
Pages (from-to)	960-969
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	3
DOIs	https://doi.org/10.1073/pnas.1814377116
State	Published - Jan 15 2019

Keywords

Aging
ERK signaling
Infertility
MicroRNA
Mouse model

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General

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10.1073/pnas.1814377116

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title = "Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo",

abstract = " DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans. Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1 S1836D/S1836D mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals.",

keywords = "Aging, ERK signaling, Infertility, MicroRNA, Mouse model",

author = "Aryal, {Neeraj K.} and Vinod Pant and Wasylishen, {Amanda R.} and Jan Parker-Thornburg and Laura Baseler and El-Naggar, {Adel K.} and Bin Liu and Awdhesh Kalia and Guillermina Lozano and Swathi Arur",

note = "Funding Information: ACKNOWLEDGMENTS. This study was supported in part by National Institutes of Health Grants GMR0198200 (to S.A.) and Cancer Center Support Grant CA016672. S.A. is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. N.K.A. is a Gigli Family Endowed Scholar at The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. Funding Information: This study was supported in part by National Institutes of Health Grants GMR0198200 (to S.A.) and Cancer Center Support Grant CA016672. S.A. is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. N.K.A. is a Gigli Family Endowed Scholar at The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All Rights Reserved.",

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doi = "10.1073/pnas.1814377116",

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AU - Aryal, Neeraj K.

AU - Pant, Vinod

AU - Wasylishen, Amanda R.

AU - Parker-Thornburg, Jan

AU - Baseler, Laura

AU - El-Naggar, Adel K.

AU - Liu, Bin

AU - Kalia, Awdhesh

AU - Lozano, Guillermina

AU - Arur, Swathi

N1 - Funding Information: ACKNOWLEDGMENTS. This study was supported in part by National Institutes of Health Grants GMR0198200 (to S.A.) and Cancer Center Support Grant CA016672. S.A. is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. N.K.A. is a Gigli Family Endowed Scholar at The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. Funding Information: This study was supported in part by National Institutes of Health Grants GMR0198200 (to S.A.) and Cancer Center Support Grant CA016672. S.A. is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center. N.K.A. is a Gigli Family Endowed Scholar at The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences. Publisher Copyright: © 2019 National Academy of Sciences. All Rights Reserved.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans. Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1 S1836D/S1836D mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals.

AB - DICER1 gene alterations and decreased expression are associated with developmental disorders and diseases in humans. Oscillation of Dicer1 phosphorylation and dephosphorylation regulates its function during the oocyte-to-embryo transition in Caenorhabditis elegans. Dicer1 is also phosphorylated upon FGF stimulation at conserved serines in mouse embryonic fibroblasts and HEK293 cells. However, whether phosphorylation of Dicer1 has a role in mammalian development remains unknown. To investigate the consequence of constitutive phosphorylation, we generated phosphomimetic knock-in mouse models by replacing conserved serines 1712 and 1836 with aspartic acids individually or together. Dicer1 S1836D/S1836D mice display highly penetrant postnatal lethality, and the few survivors display accelerated aging and infertility. Homozygous dual-phosphomimetic Dicer1 augments these defects, alters metabolism-associated miRNAs, and causes a hypermetabolic phenotype. Thus, constitutive phosphorylation of Dicer1 results in multiple pathologic processes in mice, indicating that phosphorylation tightly regulates Dicer1 function and activity in mammals.

KW - Aging

KW - ERK signaling

KW - Infertility

KW - MicroRNA

KW - Mouse model

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Equipment

Monoclonal Antibody Facility (MAF)

Cite this