PDF(Pubmed)
Abstract：
Microphthalmia, anophthalmia, and coloboma (MAC) are congenital ocular malformations causing 25% of childhood blindness. The X-linked disorder Focal Dermal Hypoplasia (FDH) is frequently associated with MAC and results from mutations in Porcn, a membrane bound O-acyl transferase required for palmitoylation of Wnts to activate multiple Wnt-dependent pathways. Wnt/β-catenin signaling is suppressed in the anterior neural plate for initiation of eye formation and is subsequently required during differentiation of the retinal pigment epithelium (RPE). Non-canonical Wnts are critical for early eye formation in frog and zebrafish. However, it is unclear whether this also applies to mammals. We performed ubiquitous conditional inactivation of Porcn in mouse around the eye field stage. In Porcn CKO , optic vesicles (OV) arrest in growth and fail to form an optic cup. Ventral proliferation is significantly decreased in the mutant OV, with a concomitant increase in apoptotic cell death. While pan-ocular transcription factors such as PAX6, SIX3, LHX2, and PAX2 are present, indicative of maintenance of OV identity, regional expression of VSX2, MITF, OTX2, and NR2F2 is downregulated. Failure of RPE differentiation in Porcn CKO is consistent with downregulation of the Wnt/β-catenin effector LEF1, starting around 2.5 days after inactivation. This suggests that Porcn inactivation affects signaling later than a potential requirement for Wnts to promote eye field formation. Altogether, our data shows a novel requirement for Porcn in regulating growth and morphogenesis of the OV, likely by controlling proliferation and survival. In FDH patients with ocular manifestations, growth deficiency during early ocular morphogenesis may be the underlying cause for microphthalmia.
摘要：
小眼症,无眼炎,结肠瘤（MAC）是先天性眼部畸形，导致25％的儿童失明。X连锁疾病局灶性真皮发育不全（FDH）通常与MAC相关，并由Porcn突变引起，膜结合的O-酰基转移酶是Wnt棕榈酰化以激活多种Wnt依赖性途径所必需的。Wnt/β-连环蛋白信号在前神经板中被抑制以启动眼睛形成，并且随后在视网膜色素上皮（RPE）的分化过程中被需要。非规范Wnts对于青蛙和斑马鱼的早期眼睛形成至关重要。然而,尚不清楚这是否也适用于哺乳动物。我们在眼场阶段周围对小鼠进行了Porcn的普遍存在的条件失活。在PorcnCKO,光学囊泡（OV）停止生长，无法形成光学杯。突变型OV的腹侧增殖显著降低,伴随着凋亡细胞死亡的增加。虽然存在泛眼转录因子，如PAX6，SIX3，LHX2和PAX2，表示保持OV身份，VSX2、MITF、OTX2和NR2F2下调。PorcnCKO中RPE分化的失败与Wnt/β-连环蛋白效应物LEF1的下调一致,在失活后约2.5天开始。这表明Porcn失活影响信号传导的时间晚于Wnt促进眼场形成的潜在要求。总之,我们的数据显示了对Porcn在调节OV的生长和形态发生方面的新需求，可能是通过控制增殖和存活。在有眼部表现的FDH患者中，早期眼部形态发生过程中的生长缺陷可能是小眼症的根本原因。
