Spatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity.
Animal Fins
/ cytology
Animals
Base Sequence
Biological Evolution
Boidae
Cattle
Chickens
Embryo, Mammalian
Embryo, Nonmammalian
Enhancer Elements, Genetic
Gene Expression Regulation, Developmental
Iguanas
Intercellular Signaling Peptides and Proteins
/ genetics
Limb Buds
/ cytology
Mice
Mice, Transgenic
Phylogeny
Protein Isoforms
/ genetics
Rabbits
Reverse Genetics
/ methods
Sequence Alignment
Sequence Homology, Nucleic Acid
Sharks
Signal Transduction
Swine
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 09 2021
21 09 2021
Historique:
received:
11
09
2020
accepted:
02
09
2021
entrez:
22
9
2021
pubmed:
23
9
2021
medline:
15
10
2021
Statut:
epublish
Résumé
Precise cis-regulatory control of gene expression is essential for normal embryogenesis and tissue development. The BMP antagonist Gremlin1 (Grem1) is a key node in the signalling system that coordinately controls limb bud development. Here, we use mouse reverse genetics to identify the enhancers in the Grem1 genomic landscape and the underlying cis-regulatory logics that orchestrate the spatio-temporal Grem1 expression dynamics during limb bud development. We establish that transcript levels are controlled in an additive manner while spatial regulation requires synergistic interactions among multiple enhancers. Disrupting these interactions shows that altered spatial regulation rather than reduced Grem1 transcript levels prefigures digit fusions and loss. Two of the enhancers are evolutionary ancient and highly conserved from basal fishes to mammals. Analysing these enhancers from different species reveal the substantial spatial plasticity in Grem1 regulation in tetrapods and basal fishes, which provides insights into the fin-to-limb transition and evolutionary diversification of pentadactyl limbs.
Identifiants
pubmed: 34548488
doi: 10.1038/s41467-021-25810-1
pii: 10.1038/s41467-021-25810-1
pmc: PMC8455560
doi:
Substances chimiques
Grem1 protein, mouse
0
Intercellular Signaling Peptides and Proteins
0
Protein Isoforms
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5557Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM124251
Pays : United States
Informations de copyright
© 2021. The Author(s).
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