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: 8435770
• 负责人: Andrew Bruce Lassar
• 金额: $ 35.98万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435770
• 关键词: Adult; Affect; Binding; Binding Sites; Bone Marrow; Cartilage; Cell Cycle; Cells; Chondrocytes; Collagen; DNA Binding; DNA Binding Domain; Defect; Development; Distal; Dwarfism; Ectopic Expression; Epiphysial cartilage; Erinaceidae; Extracellular Matrix; GATA6 transcription factor; Genes; Goals; Growth; 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; Retinal Cone; 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; public health relevance; 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（由申请方提供）：控制生长板中软骨细胞成熟的信号通路中断可导致侏儒症。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Ihh的表达。因为PTHrP表达依赖于Ihh信号传导，所以在生长板中起作用以增加或减少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具有深远的影响。我实验室最近的工作表明，转录因子GATA 6是肢芽中Sonic Hedgehog（Shh）信号的负调节因子，并且可能在生长板中发挥类似的作用，作为Indian Hedgehog（Ihh）信号的负调节因子。与后一种观点一致，我们已经发现从Col 2-Cre; GATA 6 flox/flox小鼠的所有软骨细胞中缺失GATA 6导致侏儒症和延迟的软骨细胞成熟。这些发现表明软骨细胞中GATA 6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调节的缺陷。除GATA 6外，TRPS 1是另一种在生长板中表达的含有加塔因子样DNA结合结构域的转录因子，其在毛鼻趾骨综合征（TRPS）中突变。TRPS患者有身材矮小、髋关节畸形、锥形骨骺和生长板过早闭合，反映了软骨内骨化缺陷。此外，小鼠中TPRS 1的突变导致生长板中软骨细胞肥大延迟。该提案的目的是通过确定GATA 6如何促进生长板中的软骨细胞成熟以及确定GATA 6和TPRS 1是否在促进生长板成熟中具有重叠作用，来寻求对软骨细胞肥大的转录调控的新认识。