Role of GATA6 in regulating hedgehog signaling in the growth plate

GATA6 在调节生长板中刺猬信号传导中的作用

• 批准号: 8821580
• 负责人: Andrew Bruce Lassar
• 金额: $ 36.02万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821580
• 关键词: Adult; Affect; Binding; Binding Sites; Bone Marrow; Cartilage; Cell Cycle; Cells; Chondrocytes; Collagen; Cone; DNA Binding; DNA Binding Domain; Defect; Development; Distal; Dwarfism; Ectopic Expression; Epiphysial cartilage; Erinaceidae; Extracellular Matrix; GATA6 transcription factor; Genes; Goals; Growth; Health; Hip region structure; Hypertrophy; Knowledge; Light; Limb Bud; Mesenchyme; Mus; Mutate; Mutation; Patients; Pattern; Physical condensation; Play; Primordium; Process; Production; Regulation; Regulator Genes; Relative (related person); Repression; Role; Shapes; Signal Pathway; Signal Transduction; Structure; Syndrome; Tissues; Transcription Repressor/Corepressor; Transcriptional Regulation; Work; articular cartilage; bone; bone epiphysis; inhibitor/antagonist; long bone; parathyroid hormone-related protein; postnatal; premature; prevent; smoothened signaling pathway; transcription factor

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.

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能导致侏儒症。 PTHrP 是软骨细胞成熟的关键负调节因子，其表达首先在关节周围软骨膜中观察到，随后在生长板中的圆形增殖软骨细胞中观察到。 PTHrP 表达本身依赖于生长板中肥大前软骨细胞中的 Ihh 表达。由于 PTHrP 表达依赖于 Ihh 信号传导，因此增加或减少生长板中 Ihh 信号传导的因素可能对 PTHrP 的表达和软骨细胞肥大的速率产生深远的影响。我实验室最近的工作表明，转录因子 GATA6 是肢芽中 Sonic Hedgehog (Shh) 信号传导的负调节因子，并且可能在生长板中发挥与 Indian Hedgehog (Ihh) 信号传导负调节因子类似的作用。与后一个观点一致，我们发现 Col2-Cre 中所有软骨细胞中 GATA6 的缺失； GATA6flox/flox 小鼠会导致侏儒症和软骨细胞成熟延迟。这些发现表明，软骨细胞中 GATA6 的缺失可能会失调 Ihh/PTHrP 信号环路，从而导致正常软骨细胞成熟的调节出现缺陷。除了GATA6之外，毛犀指骨综合征（TRPS）中突变的TRPS1是另一种转录因子，含有在生长板中表达的GATA因子样DNA结合域。 TRPS 患者身材矮小，髋部异常，骨骺呈锥形，生长板过早闭合，反映软骨内骨化缺陷。此外，小鼠体内TPRS1突变导致生长板软骨细胞肥大延迟。该提案的目的是通过确定 GATA6 如何促进生长板中的软骨细胞成熟，并确定 GATA6 和 TPRS1 在促进生长板成熟中是否具有重叠的作用，从而为软骨细胞肥大的转录调控提供新的线索。