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- Title
Downregulation of Grem1 expression in the distal limb mesoderm is a necessary precondition for phalanx development.
- Authors
Lancman, Joseph J.; Hasso, Sean M.; Suzuki, Takayuki; Kherdjemil, Yacine; Kmita, Marie; Ferris, Andrea; Dong, P. Duc S.; Ros, Marian A.; Fallon, John F.
- Abstract
Background: The phalanges are the final skeletal elements to form in the vertebrate limb and their identity is regulated by signaling at the phalanx forming region (PFR) located at the tip of the developing digit ray. Here, we seek to explore the relationship between PFR activity and phalanx morphogenesis, which define the most distal limb skeletal elements, and signals associated with termination of limb outgrowth. Results: As Grem1 is extinguished in the distal chick limb mesoderm, the chondrogenesis marker Aggrecan is up‐regulated in the metatarsals and phalanges. Fate mapping confirms that subridge mesoderm cells contribute to the metatarsal and phalanges when subridge Grem1 is down‐regulated. Grem1 overexpression specifically blocks chick phalanx development by inhibiting PFR activity. PFR activity and digit development are also disrupted following overexpression of a Gli3 repressor, which results in Grem1 expression in the distal limb and downregulation of Bmpr1b. Conclusions: Based on expression and fate mapping studies, we propose that downregulation of Grem1 in the distal limb marks the transition from metatarsal to phalanx development. This suggests that downregulation of Grem1 in the distal limb mesoderm is necessary for phalanx development. Grem1 downregulation allows for full PFR activity and phalanx progenitor cell commitment to digit fate. Key Findings: When Grem1 expression is down‐regulated in the distal limb mesoderm, cells fated to become metatarsal and phalanx are present in the subridge mesoderm.Overexpression of Grem1 in the chick leg with a replication defective retrovirus specifically inhibits phalanx development by inhibiting PFR activity.Gli3 modulates phalanx development by regulating PFR formation and activity in part through Bmpr1b and Grem1 expression, respectively.Down‐regulation of Grem1 in the distal limb marks the transition from metatarsal to phalanx development.Grem1 down‐regulation in the distal limb allows for PFR activity which is necessary for phalanx progenitor cell commitment to digit fate.
- Subjects
MESODERM; DOWNREGULATION; CELL determination; PROGENITOR cells; PHALANGES
- Publication
Developmental Dynamics, 2022, Vol 251, Issue 9, p1439
- ISSN
1058-8388
- Publication type
Article
- DOI
10.1002/dvdy.431