PUBLICATION
Tmem2 restricts atrioventricular canal differentiation by regulating degradation of hyaluronic acid
- Authors
- Hernandez, L., Ryckebüsch, L., Wang, C., Ling, R., Yelon, D.
- ID
- ZDB-PUB-190826-18
- Date
- 2019
- Source
- Developmental Dynamics : an official publication of the American Association of Anatomists 248(12): 1195-1210 (Journal)
- Registered Authors
- Hernandez, Lydia, Ryckebüsch, Lucile, Yelon, Deborah
- Keywords
- Cemip2, Wnt signaling, cardiac fusion, hyaluronidase, valve formation
- MeSH Terms
-
- Heart/embryology
- Animals, Genetically Modified
- Wnt Signaling Pathway/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Zebrafish Proteins/physiology*
- Animals
- Zebrafish/embryology
- Zebrafish/genetics
- Heart Ventricles/embryology*
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Membrane Proteins/physiology*
- Heart Septum/embryology*
- Signal Transduction/genetics
- Organogenesis/genetics
- Carbohydrate Metabolism/genetics
- Heart Septal Defects/genetics*
- Heart Septal Defects/metabolism
- Hyaluronic Acid/metabolism*
- Embryo, Nonmammalian
- PubMed
- 31444829 Full text @ Dev. Dyn.
Citation
Hernandez, L., Ryckebüsch, L., Wang, C., Ling, R., Yelon, D. (2019) Tmem2 restricts atrioventricular canal differentiation by regulating degradation of hyaluronic acid. Developmental Dynamics : an official publication of the American Association of Anatomists. 248(12):1195-1210.
Abstract
Background Atrioventricular valve development relies upon the precisely defined dimensions of the atrioventricular canal (AVC). Current models suggest that Wnt signaling plays an important role atop a pathway that promotes AVC development. The factors that confine AVC differentiation to the appropriate location, however, are less well understood.
Results Transmembrane protein 2 (Tmem2) is a key player in restricting AVC differentiation: in zebrafish, tmem2 mutants display an expansion of AVC characteristics, but the molecular mechanism of Tmem2 function in this context remains unclear. Through structure-function analysis, we demonstrate that the extracellular portion of Tmem2 is crucial for its role in restricting AVC boundaries. Importantly, the Tmem2 ectodomain contains regions implicated in the depolymerization of hyaluronic acid (HA). We find that tmem2 mutant hearts exhibit excess HA deposition alongside broadened distribution of Wnt signaling. Moreover, addition of ectopic hyaluronidase can restore the restriction of AVC differentiation in tmem2 mutants. Finally, we show that alteration of a residue important for HA depolymerization impairs the efficacy of Tmem2 function during AVC development.
Conclusions Taken together, our data support a model in which HA degradation, regulated by Tmem2, limits the distribution of Wnt signaling and thereby confines the differentiation of the AVC. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping