How organisms control organ size is not fully understood. We found that Syd/JIP3 is required for proper wing size in Drosophila. JIP3 mutations are associated with organ size defects in mammals. The underlying mechanisms are not well understood. We discovered that Syd/JIP3 inhibition results in a downregulation of the inhibitor of apoptosis protein 1 (Diap1) in the Drosophila wing. Correspondingly, Syd/JIP3 deficient tissues exhibit ectopic cell death and yield smaller wings. Syd/JIP3 inhibition generated similar effects in mammalian cells, indicating a conserved mechanism.

We found that Yorkie/YAP stimulates Syd/JIP3 in Drosophila and mammalian cells. Notably, Syd/JIP3 is required for the full effect of Yorkie-mediated tissue growth. Thus Syd/JIP3 regulation of Diap1 functions downstream of Yorkie/YAP to control growth.

This study provides mechanistic insights into the recent and perplexing link between JIP3 mutations and organ size defects in mammals, including in humans where de novo JIP3 variants are associated with microcephaly.

生物体如何控制器官大小尚不完全清楚。我们发现 Syd/JIP3 是果蝇适当翅膀尺寸所必需的。 JIP3突变与哺乳动物的器官大小缺陷有关。其基本机制尚不清楚。我们发现 Syd/JIP3 抑制会导致果蝇翅膀中凋亡蛋白 1 (Diap1) 抑制剂的下调。相应地，Syd/JIP3 缺陷的组织表现出异位细胞死亡并产生较小的翅膀。 Syd/JIP3 抑制在哺乳动物细胞中产生类似的效果，表明一种保守的机制。

我们发现 Yorkie/YAP 刺激果蝇和哺乳动物细胞中的 Syd/JIP3。值得注意的是，Syd/JIP3 是约克介导的组织生长的全部效果所必需的。因此 Syd/JIP3 对 Diap1 的调节在 Yorkie/YAP 下游发挥作用以控制生长。

这项研究为JIP3突变与哺乳动物（包括人类）器官大小缺陷之间最近令人费解的联系提供了机制见解，其中JIP3新生变异与小头畸形相关。