PUBLICATION
A conserved transcription factor regulatory program promotes tendon fate
- Authors
- Niu, X., Melendez, D.L., Raj, S., Cai, J., Senadeera, D., Mandelbaum, J., Shestopalov, I.A., Martin, S.D., Zon, L.I., Schlaeger, T.M., Lai, L.P., McMahon, A.P., Craft, A.M., Galloway, J.L.
- ID
- ZDB-PUB-240902-11
- Date
- 2024
- Source
- Developmental Cell 59(23): 3106-3123.e12 (Journal)
- Registered Authors
- Galloway, Jenna, McMahon, Andrew, Schlaeger, Thorsten, Zon, Leonard I.
- Keywords
- Creb1a/CREB1, Ebf1a/Ebf3a/EBF1, cAMP, chemical screen, enhancer, forskolin/colforsin, scxa, tendon, zebrafish
- MeSH Terms
-
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Cell Differentiation*/genetics
- Pluripotent Stem Cells/cytology
- Pluripotent Stem Cells/metabolism
- Cyclic AMP/metabolism
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Animals
- Mice
- Gene Expression Regulation, Developmental
- Colforsin/pharmacology
- Enhancer Elements, Genetic/genetics
- Tendons*/metabolism
- Transcription Factors*/genetics
- Transcription Factors*/metabolism
- Humans
- Cyclic AMP Response Element-Binding Protein*/genetics
- Cyclic AMP Response Element-Binding Protein*/metabolism
- PubMed
- 39216481 Full text @ Dev. Cell
Citation
Niu, X., Melendez, D.L., Raj, S., Cai, J., Senadeera, D., Mandelbaum, J., Shestopalov, I.A., Martin, S.D., Zon, L.I., Schlaeger, T.M., Lai, L.P., McMahon, A.P., Craft, A.M., Galloway, J.L. (2024) A conserved transcription factor regulatory program promotes tendon fate. Developmental Cell. 59(23):3106-3123.e12.
Abstract
Tendons, which transmit force from muscles to bones, are highly prone to injury. Understanding the mechanisms driving tendon fate would impact efforts to improve tendon healing, yet this knowledge is limited. To find direct regulators of tendon progenitor emergence, we performed a zebrafish high-throughput chemical screen. We established forskolin as a tenogenic inducer across vertebrates, functioning through Creb1a, which is required and sufficient for tendon fate. Putative enhancers containing cyclic AMP (cAMP) response elements (CREs) in humans, mice, and fish drove specific expression in zebrafish cranial and fin tendons. Analysis of these genomic regions identified motifs for early B cell factor (Ebf/EBF) transcription factors. Mutation of CRE or Ebf/EBF motifs significantly disrupted enhancer activity and specificity in tendons. Zebrafish ebf1a/ebf3a mutants displayed defects in tendon formation. Notably, Creb1a/CREB1 and Ebf1a/Ebf3a/EBF1 overexpression facilitated tenogenic induction in zebrafish and human pluripotent stem cells. Together, our work identifies the functional conservation of two transcription factors in promoting tendon fate.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping