M. Wong et al., CYR61, PRODUCT OF A GROWTH FACTOR-INDUCIBLE IMMEDIATE-EARLY GENE, REGULATES CHONDROGENESIS IN MOUSE LIMB BUD MESENCHYMAL CELLS, Developmental biology, 192(2), 1997, pp. 492-508
Chondrogenesis during embryonic skeletal development involves the cond
ensation of mesenchymal cells followed by their differentiation into c
hondrocytes. We describe herein a previously unrecognized regulator of
mammalian chondrogenesis encoded by a murine growth factor-inducible
immediate-early gene, cyr61. The Cyr61 protein is a secreted, heparin-
binding protein (379 amino acids with 38 conserved cysteines) that pro
motes cell adhesion, migration, and proliferation. The expression patt
ern of the cyr61 gene during embryogenesis is tissue specific and temp
orally regulated. Most notably, cyr61 is transiently expressed in mese
nchymal cells of both mesodermal and neuroectodermal origins undergoin
g chondrogenesis, suggesting that Cyr61 may play a role in the develop
ment of the embryonic skeleton. In this communication, we demonstrate
that the Cyr61 protein promotes chondrogenesis in micromass cultures o
f limb bud mesenchymal cells in vitro and is likely to play a similar
role in vivo based on the following observations: (1) Cyr61 is present
in the embryonic limb mesenchyme during chondrogenesis in vivo and in
vitro; (2) purified recombinant Cyr61. protein added exogenously to m
icromass cultures promotes chondrogenesis as judged by precocious expr
ession of type II collagen, increased [S-35]sulfate incorporation, and
larger Alcian blue-staining cartilage nodules; (3) Cyr61 enhances cel
l-cell aggregation, an initial step in chondrogenesis, and promotes ch
ondrogenic differentiation in cultures plated at subthreshold cell den
sities that are otherwise unable to support differentiation; and (4) n
eutralization of the endogenous Cyr61 with specific antibodies inhibit
s chondrogenesis. Taken together, these results identify Cyr61 as a no
vel player in chondrogenesis that contributes to the development of th
e mammalian embryonic skeleton. (C) 1997 Academic Press.