AUTHOR=Hasan Md. Rakibul , Koskenranta Anna , Alakurtti Kirsi , Takatalo Maarit , Rice David P. 

TITLE=RAB23 regulates musculoskeletal development and patterning

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=11

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1049131

DOI=10.3389/fcell.2023.1049131

ISSN=2296-634X

ABSTRACT=<p>RAB23 is a small GTPase which functions at the plasma membrane to regulate growth factor signaling. Mutations in <italic>RAB23</italic> cause Carpenter syndrome, a condition that affects normal organogenesis and patterning. In this study, we investigate the role of RAB23 in musculoskeletal development and show that it is required for patella bone formation and for the maintenance of tendon progenitors. The patella is the largest sesamoid bone in mammals and plays a critical role during movement by providing structural and mechanical support to the knee. <italic>Rab23</italic><sup><italic>−/−</italic></sup> mice fail to form a patella and normal knee joint. The patella is formed from <italic>Sox9</italic> and <italic>scleraxis (Scx)</italic> double-positive chondroprogenitor cells. We show that RAB23 is required for the specification of SOX9 and scleraxis double-positive patella chondroprogenitors during the formation of patella anlagen and the subsequent establishment of patellofemoral joint. We find that scleraxis and SOX9 expression are disrupted in <italic>Rab23</italic><sup><italic>−/−</italic></sup> mice, and as a result, development of the quadriceps tendons, cruciate ligaments, patella tendons, and entheses is either abnormal or lost. TGFβ-BMP signaling is known to regulate patella initiation and patella progenitor differentiation and growth. We find that the expression of TGFβR2, BMPR1, BMP4, and pSmad are barely detectable in the future patella site and in the rudimentary tendons and ligaments around the patellofemoral joint in <italic>Rab23</italic><sup><italic>−/−</italic></sup> mice. Also, we show that GLI1, SOX9, and scleraxis, which regulate entheses establishment and maturation, are weakly expressed in <italic>Rab23</italic><sup><italic>−/−</italic></sup> mice. Further analysis of the skeletal phenotype of <italic>Rab23</italic><sup><italic>−/−</italic></sup> mice showed a close resemblance to that of <italic>Tgfβ2</italic><sup><italic>−/−</italic></sup> mice, highlighting a possible role for RAB23 in regulating TGFβ superfamily signaling.</p>