The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases in zebrafish

M. Fethullah Simsek; Didar Saparov; Kemal Keseroglu; Oriana Zinani; Angad Singh Chandel; Bibek Dulal; Bal Krishan Sharma; Soling Zimik; Ertuğrul M. Özbudak

doi:10.1016/j.devcel.2024.11.003

The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases in zebrafish

M. Fethullah Simsek^*, Didar Saparov, Kemal Keseroglu, Oriana Zinani, Angad Singh Chandel, Bibek Dulal, Bal Krishan Sharma, Soling Zimik, Ertuğrul M. Özbudak^*

^*Corresponding author for this work

Cell & Developmental Biology

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

Abstract

Pulsatile activity of the extracellular signal-regulated kinase (ERK) controls several cellular, developmental, and regenerative programs. Sequential segmentation of somites along the vertebrate body axis, a key developmental program, is also controlled by ERK activity oscillation. The oscillatory expression of Her/Hes family transcription factors constitutes the segmentation clock, setting the period of segmentation. Although oscillation of ERK activity depends on Her/Hes proteins, the underlying molecular mechanism remained mysterious. Here, we show that Her/Hes proteins physically interact with and stabilize dual-specificity phosphatases (Dusp) of ERK, resulting in oscillations of Dusp4 and Dusp6 proteins. Pharmaceutical and genetic inhibition of Dusp activity disrupt ERK activity oscillation and somite segmentation in zebrafish. Our results demonstrate that post-translational interactions of Her/Hes transcription factors with Dusp phosphatases establish the fundamental vertebrate body plan. We anticipate that future studies will identify currently unnoticed post-translational control of ERK pulses in other systems.

Original language	English (US)
Pages (from-to)	669-678.e6
Journal	Developmental Cell
Volume	60
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2024.11.003
State	Published - Mar 10 2025

Funding

We thank Hannah Seawall, Matthew Kofron, Cincinnati Children\u2019s Imaging Core, and Cincinnati Children\u2019s Veterinary Services for technical assistance; Scott Holley, Ryoichiro Kageyama, and Mohammad Azam for providing plasmids; Eslim Esra Alpay and Cassandra McDaniel for discussions; and Rafi Kopan, Mohammad Azam, Kana Ishimatsu, Aaron Zorn, and Saulius Sumanas for providing feedback on the manuscript. Funding: this work was funded by an NIH grant ( R01HD103623 ) to E.M.\u00D6.

Keywords

Dusp
ERK
clock
oscillation
pattern formation
post-translational
segmentation
somitogenesis
wave

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2024.11.003

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title = "The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases in zebrafish",

abstract = "Pulsatile activity of the extracellular signal-regulated kinase (ERK) controls several cellular, developmental, and regenerative programs. Sequential segmentation of somites along the vertebrate body axis, a key developmental program, is also controlled by ERK activity oscillation. The oscillatory expression of Her/Hes family transcription factors constitutes the segmentation clock, setting the period of segmentation. Although oscillation of ERK activity depends on Her/Hes proteins, the underlying molecular mechanism remained mysterious. Here, we show that Her/Hes proteins physically interact with and stabilize dual-specificity phosphatases (Dusp) of ERK, resulting in oscillations of Dusp4 and Dusp6 proteins. Pharmaceutical and genetic inhibition of Dusp activity disrupt ERK activity oscillation and somite segmentation in zebrafish. Our results demonstrate that post-translational interactions of Her/Hes transcription factors with Dusp phosphatases establish the fundamental vertebrate body plan. We anticipate that future studies will identify currently unnoticed post-translational control of ERK pulses in other systems.",

keywords = "Dusp, ERK, clock, oscillation, pattern formation, post-translational, segmentation, somitogenesis, wave",

author = "Simsek, {M. Fethullah} and Didar Saparov and Kemal Keseroglu and Oriana Zinani and Chandel, {Angad Singh} and Bibek Dulal and Sharma, {Bal Krishan} and Soling Zimik and {\"O}zbudak, {Ertuğrul M.}",

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doi = "10.1016/j.devcel.2024.11.003",

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AU - Simsek, M. Fethullah

AU - Saparov, Didar

AU - Keseroglu, Kemal

AU - Zinani, Oriana

AU - Chandel, Angad Singh

AU - Dulal, Bibek

AU - Sharma, Bal Krishan

AU - Zimik, Soling

AU - Özbudak, Ertuğrul M.

PY - 2025/3/10

Y1 - 2025/3/10

N2 - Pulsatile activity of the extracellular signal-regulated kinase (ERK) controls several cellular, developmental, and regenerative programs. Sequential segmentation of somites along the vertebrate body axis, a key developmental program, is also controlled by ERK activity oscillation. The oscillatory expression of Her/Hes family transcription factors constitutes the segmentation clock, setting the period of segmentation. Although oscillation of ERK activity depends on Her/Hes proteins, the underlying molecular mechanism remained mysterious. Here, we show that Her/Hes proteins physically interact with and stabilize dual-specificity phosphatases (Dusp) of ERK, resulting in oscillations of Dusp4 and Dusp6 proteins. Pharmaceutical and genetic inhibition of Dusp activity disrupt ERK activity oscillation and somite segmentation in zebrafish. Our results demonstrate that post-translational interactions of Her/Hes transcription factors with Dusp phosphatases establish the fundamental vertebrate body plan. We anticipate that future studies will identify currently unnoticed post-translational control of ERK pulses in other systems.

AB - Pulsatile activity of the extracellular signal-regulated kinase (ERK) controls several cellular, developmental, and regenerative programs. Sequential segmentation of somites along the vertebrate body axis, a key developmental program, is also controlled by ERK activity oscillation. The oscillatory expression of Her/Hes family transcription factors constitutes the segmentation clock, setting the period of segmentation. Although oscillation of ERK activity depends on Her/Hes proteins, the underlying molecular mechanism remained mysterious. Here, we show that Her/Hes proteins physically interact with and stabilize dual-specificity phosphatases (Dusp) of ERK, resulting in oscillations of Dusp4 and Dusp6 proteins. Pharmaceutical and genetic inhibition of Dusp activity disrupt ERK activity oscillation and somite segmentation in zebrafish. Our results demonstrate that post-translational interactions of Her/Hes transcription factors with Dusp phosphatases establish the fundamental vertebrate body plan. We anticipate that future studies will identify currently unnoticed post-translational control of ERK pulses in other systems.

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KW - ERK

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KW - somitogenesis

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The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases in zebrafish

Abstract

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Keywords

ASJC Scopus subject areas

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