Role of GATA6 in regulating hedgehog signaling in the growth plate

描述（由申请人提供）：生长板中控制软骨细胞成熟的信号通路的破坏可导致侏儒症。PTHrP是软骨细胞成熟的关键负调控因子，首先在关节周围软骨膜中观察到表达，随后在生长板中的圆形增殖软骨细胞中观察到表达。生长板中增生性软骨细胞中PTHrP的表达本身依赖于Ihh的表达。由于PTHrP的表达依赖于Ihh信号传导，生长板中增加或减少Ihh信号传导的因子可能对PTHrP的表达和软骨细胞肥大率都有深远的影响。我的实验室最近的工作表明转录因子GATA6是肢体芽中Sonic Hedgehog （Shh）信号的负调节因子，并且可能在生长板中发挥与印度Hedgehog （Ihh）信号负调节因子相似的作用。与后一种观点一致，我们发现Col2-Cre中所有软骨细胞中GATA6的缺失；GATA6flox/flox小鼠导致侏儒症和软骨细胞成熟延迟。这些发现提示，软骨细胞中GATA6的缺失可能会使Ihh/PTHrP信号通路失调，从而导致正常软骨细胞成熟的调控出现缺陷。除了GATA6外，TRPS1是另一种在生长板中表达的含有GATA因子样DNA结合域的转录因子，在Tricho-rhino-phalangeal syndrome （TRPS）中发生突变。TRPS患者身材矮小，髋关节异常，骨骺呈锥形，生长板过早闭合，反映软骨内成骨缺陷。此外，小鼠TPRS1突变导致生长板软骨细胞肥大延迟。本研究旨在通过确定GATA6如何促进生长板中的软骨细胞成熟，以及GATA6和TPRS1在促进生长板成熟中是否有重叠的作用，来阐明软骨细胞肥大的转录调控。

DESCRIPTION (provided by applicant): Disruption of the signaling pathways that control chondrocyte maturation in the growth plate can result in dwarfism. PTHrP is a key negative regulator of chondrocyte maturation, whose expression is first observed in the periarticular perichondrium and subsequently in round proliferative chondrocytes in the growth plate. PTHrP expression is itself dependent upon Ihh expression in prehypertrophic chondrocytes in the growth plate. Because PTHrP expression is dependent upon Ihh signaling, factors that act to either increase or decrease Ihh signaling in the growth plate could potentially have a profound effect on both the expression of PTHrP and the rate of chondrocyte hypertrophy. Recent work in my lab has indicated that the transcription factor GATA6 is a negative regulator of Sonic Hedgehog (Shh) signaling in the limb bud, and may play a similar role in the growth plate as a negative regulator of Indian Hedgehog (Ihh) signaling. Consistent with this latter notion, we have found that deletion of GATA6 from all chondrocytes in Col2-Cre; GATA6flox/flox mice results in both dwarfism and delayed chondrocyte maturation. These findings suggest that loss of GATA6 in chondrocytes may disregulate the Ihh/PTHrP signaling loop, which would result in defects in the regulation of normal chondrocyte maturation. In addition to GATA6, TRPS1 which is mutated in Tricho-rhino-phalangeal syndrome (TRPS) is another transcription factor containing a GATA factor-like DNA binding domain that is expressed in the growth plate. Patients with TRPS have short stature, hip abnormalities, cone- shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. In addition, mutation of TPRS1 in mice leads to delayed chondrocyte hypertrophy in the growth plate. The aims of this proposal seek to shed new light on the transcriptional regulation of chondrocyte hypertrophy, by determining both how GATA6 acts to promote chondrocyte maturation in the growth plate and determine whether GATA6 and TPRS1 share overlapping roles in promoting growth plate maturation.