Temporal misexpression ofEn1during limb development causes distinct phenotypes

Alessa R. Ringel, Andreas Magg, Natalia Benetti, Robert Schöpflin, Mira Kühnlein, Asita Carola Stiege, Ute Fischer, Lars Wittler, Stephan Lorenz, Stefan Mundlos, Lila Allou
2024 · doi:10.1101/2024.08.06.606766
preprint OA: closed CC-BY-NC-ND-4.0
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This study examined how spatiotemporal regulation of the developmental gene Engrailed-1 (En1) during mouse limb development is maintained after Maenli lncRNA activity drops, focusing on embryonic days E9.5 to E11.5. Using in vivo CRISPR editing, the authors identified two intergenic enhancer elements, LSEE1 and LSEE2, that sustain En1 expression at E10.5 and E11.5, and found that mice lacking these enhancers show only a subset of the limb malformations seen in En1 and Maenli mutants. The authors explicitly note a caveat that enhancer loss produces distinct but incomplete phenotypes compared with full En1 or Maenli disruption, consistent with temporal misexpression leading to different outcomes. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

The precise spatiotemporal regulation of developmental genes is required for proper organogenesis. Engrailed-1 ( En1 ) is essential for dorsal-ventral patterning during mouse limb development from embryonic day E9.5 to E11.5. Previously, we identified the long non-coding RNA locus Maenli , which drives limb-specific En1 expression at E9.5. In this study, we investigated the regulatory mechanisms sustaining En1 expression at later developmental stages when Maenli transcriptional activity is drastically reduced. Using in vivo CRISPR editing, we identified two intergenic enhancer elements, LSEE1 and LSEE2, that maintain En1 expression at E10.5 and E11.5. Mice lacking these enhancers exhibit only a subset of the limb malformations observed in En1 and Maenli mutants, indicating that the timing of En1 misexpression causes distinct phenotypes. These findings underscore the role of temporally restricted activities of cis -regulatory elements, including lncRNA loci and enhancers, in modulating gene expression and explaining subtle differences in complex disease phenotypes.
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Abstract The precise spatiotemporal regulation of developmental genes is required for proper organogenesis. Engrailed-1 (En1) is essential for dorsal-ventral patterning during mouse limb development from embryonic day E9.5 to E11.5. Previously, we identified the long non-coding RNA locus Maenli, which drives limb-specific En1 expression at E9.5. In this study, we investigated the regulatory mechanisms sustaining En1 expression at later developmental stages when Maenli transcriptional activity is drastically reduced. Using in vivo CRISPR editing, we identified two intergenic enhancer elements, LSEE1 and LSEE2, that maintain En1 expression at E10.5 and E11.5. Mice lacking these enhancers exhibit only a subset of the limb malformations observed in En1 and Maenli mutants, indicating that the timing of En1 misexpression causes distinct phenotypes. These findings underscore the role of temporally restricted activities of cis-regulatory elements, including lncRNA loci and enhancers, in modulating gene expression and explaining subtle differences in complex disease phenotypes. Competing Interest Statement The authors have declared no competing interest. Footnotes This is the updated version of the manuscript.

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