ACSL4 inhibits synapse growth by attenuating BMP signaling via endocytic recycling of its receptors. Yan Huang, Zhihua Liu, Qifu Wang, Yong Q. Zhang. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.

   Mutations of acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that converts long chain fatty acids to acyl-CoAs, result in non-syndromic X-linked mental retardation (MRX). Using the Drosophila neuromuscular junction (NMJ) as a model, we found that the Drosophila homolog dAcsl inhibits synaptic growth by attenuating bone morphogenetic protein (BMP) signaling, a major growth-promoting pathway at NMJ synapses. Specifically, dAcsl mutants exhibited NMJ overgrowth that was suppressed by reducing the doses of the BMP pathway components. There was an increased level of activated BMP receptor Thickveins (Tkv) and phosphorylated Mad, the effector of the BMP signaling in NMJ terminals. Furthermore, the receptor Tkv accumulated in early endosomes but reduced in recycling endosomes, together with the expression pattern of Rab11-positive recycling endosomes altered in dAcsl synapses. This study reveals a novel mechanism whereby dAcsl restrains BMP signaling at NMJ synapses by facilitating Rab11-dependent endosomal recycling of BMP receptors and offers new insight into the pathogenesis of ACSL4-related MRX.