Gupta Mohona, Lewis Tylor R, Stuck Michael W, Spencer William J, Klementieva Natalia V, Arshavsky Vadim Y, Pazour Gregory J
Program in Molecular Medicine, University of Massachusetts Chan Medical School, Suite 213 Biotech II, 373 Plantation Street, Worcester, MA 01605, USA.
Morningside Graduate School of Biological Sciences, University of Massachusetts Chan Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
J Cell Sci. 2025 Feb 15;138(4). doi: 10.1242/jcs.263814. Epub 2025 Feb 21.
In humans, inositol polyphosphate-5-phosphatase E (INPP5E) mutations cause retinal degeneration as part of Joubert and MORM syndromes and can also cause non-syndromic blindness. In mice, mutations cause a spectrum of brain, kidney and other anomalies and prevent the formation of photoreceptor outer segments. To further explore the function of Inpp5e in photoreceptors, we generated conditional and inducible knockouts of mouse Inpp5e where the gene was deleted either during outer segment formation or after outer segments were fully formed. In both cases, the loss of Inpp5e led to severe defects in photoreceptor outer segment morphology and ultimately photoreceptor cell loss. The primary morphological defect consisted of outer segment shortening and reduction in the number of newly forming discs at the outer segment base. This was accompanied by structural abnormalities of the Golgi, mislocalized rhodopsin and an accumulation of extracellular vesicles. In addition, knockout cells showed disruption of the actin network. Together, these data demonstrate that Inpp5e plays a crucial role in maintaining the outer segment and the normal process of outer segment renewal depends on the activity of this enzyme.
在人类中，肌醇多磷酸-5-磷酸酶E（INPP5E）突变会导致视网膜变性，这是乔伯特综合征和MORM综合征的一部分，也可导致非综合征性失明。在小鼠中，突变会导致一系列大脑、肾脏和其他异常，并阻止光感受器外节的形成。为了进一步探索Inpp5e在光感受器中的功能，我们构建了小鼠Inpp5e的条件性和诱导性敲除模型，其中该基因在外节形成期间或外节完全形成后被删除。在这两种情况下，Inpp5e的缺失都导致光感受器外节形态严重缺陷，并最终导致光感受器细胞丢失。主要的形态学缺陷包括外节缩短和外节基部新形成盘状结构数量减少。这伴随着高尔基体的结构异常、视紫红质定位错误以及细胞外囊泡的积累。此外，敲除细胞显示肌动蛋白网络受到破坏。总之，这些数据表明Inpp5e在维持外节中起关键作用，外节更新的正常过程依赖于该酶的活性。
