The Lin28/let-7 Pathway Regulates the Mammalian Caudal Body Axis Elongation Program

Daisy A. Robinton; Jérome Chal; Edroaldo Lummertz da Rocha; Areum Han; Alena V. Yermalovich; Masayuki Oginuma; Thorsten M. Schlaeger; Patricia Sousa; Antony Rodriguez; Achia Urbach; Olivier Pourquié; George Q. Daley

doi:10.1016/j.devcel.2018.12.016

The Lin28/let-7 Pathway Regulates the Mammalian Caudal Body Axis Elongation Program

Daisy A. Robinton, Jérome Chal, Edroaldo Lummertz da Rocha, Areum Han, Alena V. Yermalovich, Masayuki Oginuma, Thorsten M. Schlaeger, Patricia Sousa, Antony Rodriguez, Achia Urbach, Olivier Pourquié, George Q. Daley

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

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

50 Scopus citations

Abstract

The heterochronic genes Lin28a/b and let-7 regulate invertebrate development, but their functions in patterning the mammalian body plan remain unexplored. Here, we describe how Lin28/let-7 influence caudal vertebrae number during body axis formation. We found that FoxD1-driven overexpression of Lin28a strikingly increased caudal vertebrae number and tail bud cell proliferation, whereas its knockout did the opposite. Lin28a overexpression downregulated the neural marker Sox2, causing a pro-mesodermal phenotype with a decreased proportion of neural tissue relative to nascent mesoderm. Manipulating Lin28a and let-7 led to opposite effects, and manipulating Lin28a's paralog, LIN28B caused similar yet distinct phenotypes. These findings suggest that Lin28/let-7 play a role in the regulation of tail length through heterochrony of the body plan. We propose that the Lin28/let-7 pathway controls the pool of caudal progenitors during tail development, promoting their self-renewal and balancing neural versus mesodermal cell fate decisions.

Original language	English
Pages (from-to)	396-405.e3
Journal	Developmental Cell
Volume	48
Issue number	3
DOIs	https://doi.org/10.1016/j.devcel.2018.12.016
State	Published - 11 Feb 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Funding

G.Q.D. was supported by NIH grant R01GM107536 and the Howard Hughes Medical Institute . We are grateful to Drs. Ho-Chou Tu, Jihan Osborne, and Michael C.F. Chen for their invaluable insights and discussion. Jessica Barragan, Sam Ross, and ARCH assisted with animal maintenance. Erin Snay assisted in X-ray imaging the animals. Renee Rubio, Derrick DeConti, and The Center for Cancer Computational Biology at Dana-Farber Cancer Institute assisted with study design and data interpretation of the RNA-seq experiments. Rod Bronson from the Rodent Histopathology core at Harvard Medical School did the initial mouse tissue pathology. Dr. Robert Rowe thoughtfully read the manuscript and provided insightful comments. For qRT-PCR of mature let-7 miRNA, we used Qiagen miScript target as described by the manufacturer. Bioanalyzer analysis was performed in the BCM IDDRC Molecular Genetics Core supported by National Institutes of Health Award NIH-P30-HD 18655. RNA-seq libraries were prepared by The Center for Cancer Computational Biology (CCCB), Dana-Farber Cancer Institute, Boston MA using NEB Ultra Directional RNA library prep kit for Illumina and sequenced using Illumina NextSeq 500 Single Read 75. Initial data analysis and quality control was performed by Derrick DeConti at CCCB. The GEO accession number for this dataset is GSE123193 . Ingenuity Pathway Analysis was used to determine biological pathways significantly represented in the dataset. Data analysis relating to enrichment was performed using gene enrichment tests using hypergeometric tests.

Funders	Funder number
National Institutes of Health	NIH-P30-HD 18655, R01GM107536
Howard Hughes Medical Institute
National Cancer Institute	F99CA212487

Keywords

Lin28
Sox2
body axis elongation
body plan
cell fate
development
heterochrony
let-7 miRNA
somitogenesis
tail bud

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10.1016/j.devcel.2018.12.016

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title = "The Lin28/let-7 Pathway Regulates the Mammalian Caudal Body Axis Elongation Program",

abstract = "The heterochronic genes Lin28a/b and let-7 regulate invertebrate development, but their functions in patterning the mammalian body plan remain unexplored. Here, we describe how Lin28/let-7 influence caudal vertebrae number during body axis formation. We found that FoxD1-driven overexpression of Lin28a strikingly increased caudal vertebrae number and tail bud cell proliferation, whereas its knockout did the opposite. Lin28a overexpression downregulated the neural marker Sox2, causing a pro-mesodermal phenotype with a decreased proportion of neural tissue relative to nascent mesoderm. Manipulating Lin28a and let-7 led to opposite effects, and manipulating Lin28a's paralog, LIN28B caused similar yet distinct phenotypes. These findings suggest that Lin28/let-7 play a role in the regulation of tail length through heterochrony of the body plan. We propose that the Lin28/let-7 pathway controls the pool of caudal progenitors during tail development, promoting their self-renewal and balancing neural versus mesodermal cell fate decisions.",

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AU - Yermalovich, Alena V.

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AU - Schlaeger, Thorsten M.

AU - Sousa, Patricia

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AU - Pourquié, Olivier

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The Lin28/let-7 Pathway Regulates the Mammalian Caudal Body Axis Elongation Program

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Bibliographical note

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Keywords

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