Heterochronic regulation of lung development via the Lin28-Let-7 pathway

Nelly Komarovsky Gulman; Leah Armon; Tali Shalit; Achia Urbach

doi:10.1096/fj.201802702R

Heterochronic regulation of lung development via the Lin28-Let-7 pathway

Nelly Komarovsky Gulman, Leah Armon, Tali Shalit, Achia Urbach

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

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

11 Scopus citations

Abstract

The heterochronic gene Lin28 regulates diverse developmental processes. It was shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been elucidated. Here, we showed that Lin28A overexpression prevents normal lung development via the inhibition of the Let-7 micro RNAs, thus causing the perinatal lethality. We further found that Lin28A overexpression in lung mesenchymal cells, but not epithelial cells, is sufficient to recapitulate the lung phenotype. Moreover, we defined the specific time window wherein Lin28A expression exerts its effect. Deep characterization of the transgenic lungs suggests that the Lin28A-Let-7 pathway delays the transition from one developmental stage to another but does not completely abrogate the differentiation capacity of the lung progenitor cells. Finally, we suggested that the effect of Lin28A-Let-7 on embryonic lung development is mediated at least in part through the TGF-p1-signaling pathway. Altogether, these findings define for the first time the Lin28-Let-7 pathway as a critical heterochronic regulator of lung development.—Komarovsky Gulman, N., Armon, L., Shalit, T., Urbach, A. Heterochronic regulation of lung development via the Lin28-Let-7 pathway. FASEB J. 33, 12008-12018 (2019). www.fasebj.org.

Original language	English
Pages (from-to)	12008-12018
Number of pages	11
Journal	FASEB Journal
Volume	33
Issue number	11
Early online date	7 Aug 2019
DOIs	https://doi.org/10.1096/fj.201802702R
State	Published - 1 Nov 2019

Bibliographical note

Publisher Copyright:
© FASEB

Funding

The authors thank Dr. Daley (Boston Children's Hospital, Boston, MA, USA) for kindly providing the Lox‐stop‐Lox‐TetOn‐Lin28A mice, Dr. Avi Jacob and Dr. Irit Shoval (Scientific Equipment Center, Bar‐Ilan University) for helping with the confocal microscopy analysis, and the staff at the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine (Weizmann Institute of Science) for performing the RNA sequencing. This work was funded by Israel Science Foundation (ISF) Grants 1389/15 and 1204/17. The authors declare no conflicts of interest. The authors thank Dr. Daley (Boston Children's Hospital, Boston, MA, USA) for kindly providing the Lox-stop-Lox-TetOn-Lin28A mice, Dr. Avi Jacob and Dr. Irit Shoval (Scientific Equipment Center, Bar-Ilan University) for helping with the confocal microscopy analysis, and the staff at the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine (Weizmann Institute of Science) for performing the RNA sequencing. This work was funded by Israel Science Foundation (ISF) Grants 1389/15 and 1204/17. The authors declare no conflicts of interest.

Funders	Funder number
Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine
Weizmann Institute of Science
Israel Science Foundation	1204/17, 1389/15

Keywords

heterochronic genes
miRNA
organogenesis

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abstract = "The heterochronic gene Lin28 regulates diverse developmental processes. It was shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been elucidated. Here, we showed that Lin28A overexpression prevents normal lung development via the inhibition of the Let-7 micro RNAs, thus causing the perinatal lethality. We further found that Lin28A overexpression in lung mesenchymal cells, but not epithelial cells, is sufficient to recapitulate the lung phenotype. Moreover, we defined the specific time window wherein Lin28A expression exerts its effect. Deep characterization of the transgenic lungs suggests that the Lin28A-Let-7 pathway delays the transition from one developmental stage to another but does not completely abrogate the differentiation capacity of the lung progenitor cells. Finally, we suggested that the effect of Lin28A-Let-7 on embryonic lung development is mediated at least in part through the TGF-p1-signaling pathway. Altogether, these findings define for the first time the Lin28-Let-7 pathway as a critical heterochronic regulator of lung development.—Komarovsky Gulman, N., Armon, L., Shalit, T., Urbach, A. Heterochronic regulation of lung development via the Lin28-Let-7 pathway. FASEB J. 33, 12008-12018 (2019). www.fasebj.org.",

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Heterochronic regulation of lung development via the Lin28-Let-7 pathway

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Keywords

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