Modeling spinal muscular atrophy in Drosophila.

Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a...

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Autores principales:	Howard Chia-Hao Chang, Douglas N Dimlich, Takakazu Yokokura, Ashim Mukherjee, Mark W Kankel, Anindya Sen, Vasanthi Sridhar, Tudor A Fulga, Anne C Hart, David Van Vactor, Spyros Artavanis-Tsakonas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dafc3ca54a234f99bc04d8a718fc5c1a
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spelling	oai:doaj.org-article:dafc3ca54a234f99bc04d8a718fc5c1a2021-11-25T06:18:37ZModeling spinal muscular atrophy in Drosophila.1932-620310.1371/journal.pone.0003209https://doaj.org/article/dafc3ca54a234f99bc04d8a718fc5c1a2008-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18791638/?tool=EBIhttps://doaj.org/toc/1932-6203Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets.Howard Chia-Hao ChangDouglas N DimlichTakakazu YokokuraAshim MukherjeeMark W KankelAnindya SenVasanthi SridharTudor A FulgaAnne C HartDavid Van VactorSpyros Artavanis-TsakonasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 9, p e3209 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Howard Chia-Hao Chang Douglas N Dimlich Takakazu Yokokura Ashim Mukherjee Mark W Kankel Anindya Sen Vasanthi Sridhar Tudor A Fulga Anne C Hart David Van Vactor Spyros Artavanis-Tsakonas Modeling spinal muscular atrophy in Drosophila.
description	Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets.
format	article
author	Howard Chia-Hao Chang Douglas N Dimlich Takakazu Yokokura Ashim Mukherjee Mark W Kankel Anindya Sen Vasanthi Sridhar Tudor A Fulga Anne C Hart David Van Vactor Spyros Artavanis-Tsakonas
author_facet	Howard Chia-Hao Chang Douglas N Dimlich Takakazu Yokokura Ashim Mukherjee Mark W Kankel Anindya Sen Vasanthi Sridhar Tudor A Fulga Anne C Hart David Van Vactor Spyros Artavanis-Tsakonas
author_sort	Howard Chia-Hao Chang
title	Modeling spinal muscular atrophy in Drosophila.
title_short	Modeling spinal muscular atrophy in Drosophila.
title_full	Modeling spinal muscular atrophy in Drosophila.
title_fullStr	Modeling spinal muscular atrophy in Drosophila.
title_full_unstemmed	Modeling spinal muscular atrophy in Drosophila.
title_sort	modeling spinal muscular atrophy in drosophila.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/dafc3ca54a234f99bc04d8a718fc5c1a
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Modeling spinal muscular atrophy in Drosophila.

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