Regulation of Digit Patterning and Chondrogenesis by BMP Antagonists
Evolutionary Cell and Developmental Biology (Zoology)
Cell Biology
Final Report Abstract
The developing vertebrate limb constitutes an excellent model system to study signaling pathways and gene regulatory networks in the context of morphogenesis, patterning and tissue growth. Undifferentiated limb bud mesenchymal progenitors (LMPs) residing in the distal subectodermal mesenchyme undergo proliferative expansion, while SOX9-positive cells in the core mesenchyme are more specified and committed towards the osteo-chondrogenic fate. However, the cellular identity of the LMP pool and the underlying molecular interactions governing its maintenance were not clear. This study combines flow cytometric and transcriptome analyses to identify and characterize five distinct cell populations in the early limb bud. The transcriptional signatures combined with experimental manipulation of two immature SOX9-negative LMP populations of the chondrogenic lineage reveals their dependence on morphogenetic SHH and FGF signaling, while precocious exposure to BMPs triggers apoptosis and depletion of the progenitor pool. The more immature LMP population resides in the posterior-distal mesenchyme and is protected from BMP activity by GREMLIN1-mediated BMP antagonism. This is in sharp contrast to osteo-chondrogenic progenitors in the core mesenchyme of early limb buds, which rely on BMP signaling to progress in the chondrogenic program. Unexpectedly, an independent population representing part of the myogenic lineage that is devoid of chondrogenic potential was identified in the limb bud. This study offers functional evidence for the signaling molecules balancing proliferation and specification at the beginning of chondrogenesis and highlights that distinct mesenchymal progenitors respond differentially rather than uniformly to morphogenetic stimuli.
Publications
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(2017). Ontogenic Identification and Analysis of Mesenchymal Stromal Cell Populations during Mouse Limb and Long Bone Development. Stem Cell Reports 9, 1124-1138
Nusspaumer, G., Jaiswal, S., Barbero, A., Reinhardt, R., Ishay Ronen, D., Haumer, A., Lufkin, T., Martin, I., and Zeller, R.
