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Human Molecular Genetics Advance Access originally published online on July 19, 2009
Human Molecular Genetics 2009 18(20):3894-3905; doi:10.1093/hmg/ddp332
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Analyses of mental dysfunction-related ACSl4 in Drosophila reveal its requirement for Dpp/BMP production and visual wiring in the brain

Yi Zhang1,2, Di Chen1,2 and Zhaohui Wang1,*

1 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beichen Xilu #1, Beijing 100101, People's Republic of China and 2 Graduate School, Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100039, People's Republic of China

* To whom correspondence should be addressed. +86 1064807785; Email: zhwang{at}genetics.ac.cn

Received June 8, 2009; Accepted July 16, 2009

Long-chain acyl-CoA synthetases (ACSLs) convert long-chain fatty acids to acyl-CoAs, the activated substrates essential in various metabolic and signaling pathways. Mutations in ACSL4 are associated with non-syndromic X-linked mental retardation (MRX). However, the developmental functions of ACSL4 and how it is involved in the pathogenesis of MRX remain largely unknown. The Drosophila ACSL-like protein is highly homologous to human ACSL3 and ACSL4, and we designate it as dAcsl. In this study, we demonstrate that dAcsl and ACSL4 are highly conserved in terms of ACSL4's ability to substitute the functions of dAcsl in organismal viability, lipid storage and the neural wiring in visual center. In neurodevelopment, decapentaplegic (Dpp, a BMP-like molecule) production diminished specifically in the larval brain of dAcsl mutants. Consistent with the Dpp reduction, the number of glial cells and neurons dramatically decreased and the retinal axons mis-targeted in the visual cortex. All these defects in Drosophila brain were rescued by the wild-type ACSL4 but not by the mutant products found in MRX patients. Interestingly, expression of an MRX-associated ACSL4 mutant form in a wild-type background led to the lesions in visual center, suggesting a dominant negative effect. These findings validate Drosophila as a model system to reveal the connection between ACSL4 and BMP pathway in neurodevelopment, and to infer the pathogenesis of ACSL4-related MRX.


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