Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells.
Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells.
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DOI：
10.1186/jbiol29
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发表时间：
2005
影响因子：
--
通讯作者：
Sommer L
中科院分区：
文献类型：
--
作者：
Ittner LM;Wurdak H;Schwerdtfeger K;Kunz T;Ille F;Leveen P;Hjalt TA;Suter U;Karlsson S;Hafezi F;Born W;Sommer L
眼的发育在一定程度上依赖于由神经脊(NC)衍生的眼周间充质，但NC细胞在哺乳动物眼发育中的命运以及协调眼部结构形成的信号尚不清楚。在这里，我们揭示了不同的NC对眼睛的前部和后部间充质结构的贡献，并表明这些细胞中的转化生长因子β信号对正常的眼睛发育至关重要。在前眼，转录因子Pitx2和Foxc1在NC来源的角膜和控制眼压的房角结构中的表达需要从晶状体释放的转化生长因子β2。转化生长因子β增强Foxc1和诱导细胞培养中Pitx2的表达。与携带PITX2和FOXC1突变的患者一样，NC细胞中转化生长因子β信号的失活会导致人类阿森菲尔德-里格畸形所特有的眼部缺陷。在后眼，转化生长因子β信号的NC细胞特异性失活导致了一种让人想起人类疾病持续性初级玻璃体增生症的情况。作为第二个效应，突变小鼠的视网膜图案也会受到干扰。在发育中的眼睛中，晶状体起着转化生长因子β信号中心的作用，控制着来自NC的眼睛结构的发育。转化生长因子β信号转导通路缺陷会干扰晶状体前的NC细胞分化和存活，以及晶状体后正常的组织形态发生和构图。与人类发育性眼部疾病的相似性表明，眼NC衍生品中转化生长因子β信号的缺陷调节参与了这些疾病的病理生理过程。
Development of the eye depends partly on the periocular mesenchyme derived from the neural crest (NC), but the fate of NC cells in mammalian eye development and the signals coordinating the formation of ocular structures are poorly understood. Here we reveal distinct NC contributions to both anterior and posterior mesenchymal eye structures and show that TGFβ signaling in these cells is crucial for normal eye development. In the anterior eye, TGFβ2 released from the lens is required for the expression of transcription factors Pitx2 and Foxc1 in the NC-derived cornea and in the chamber-angle structures of the eye that control intraocular pressure. TGFβ enhances Foxc1 and induces Pitx2 expression in cell cultures. As in patients carrying mutations in PITX2 and FOXC1, TGFβ signal inactivation in NC cells leads to ocular defects characteristic of the human disorder Axenfeld-Rieger's anomaly. In the posterior eye, NC cell-specific inactivation of TGFβ signaling results in a condition reminiscent of the human disorder persistent hyperplastic primary vitreous. As a secondary effect, retinal patterning is also disturbed in mutant mice. In the developing eye the lens acts as a TGFβ signaling center that controls the development of eye structures derived from the NC. Defective TGFβ signal transduction interferes with NC-cell differentiation and survival anterior to the lens and with normal tissue morphogenesis and patterning posterior to the lens. The similarity to developmental eye disorders in humans suggests that defective TGFβ signal modulation in ocular NC derivatives contributes to the pathophysiology of these diseases.