The Drosophila fragile X-related gene regulates axoneme differentiation during spermatogenesis

Zhang, Yong Q.; Matthies, Heinrich J.G.; Mancuso, Joel; Andrews, Hillary K.; Woodruff, Elvin; Friedman, David; Broadie, Kendal

doi:10.1016/j.ydbio.2004.02.010

Cited by 68 publications

(59 citation statements)

References 55 publications

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“…An additional 27% have only one central pair in these later stages. A specific disruption of the central pair microtubules which becomes progressively more pronounced as spermatid differentiation proceeds was also reported in a mutant of the Drosophila fragile X mental retardation gene (fxr, also called fmr1; Zhang et al, 2004). fxr encodes an RNA-binding translational regulator that was proposed to regulate microtubule stability in the testes by controlling the translation of specific proteins.…”

Section: The Role Of Bld10 In the Assembly Of The Central Apparatus Omentioning

confidence: 87%

DrosophilaBld10 Is a Centriolar Protein That Regulates Centriole, Basal Body, and Motile Cilium Assembly

Mottier-Pavie

Megraw

2009

MBoC

107

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Cilia and flagella play multiple essential roles in animal development and cell physiology. Defective cilium assembly or motility represents the etiological basis for a growing number of human diseases. Therefore, how cilia and flagella assemble and the processes that drive motility are essential for understanding these diseases. Here we show that Drosophila Bld10, the ortholog of Chlamydomonas reinhardtii Bld10p and human Cep135, is a ubiquitous centriolar protein that also localizes to the spermatid basal body. Mutants that lack Bld10 assemble centrioles and form functional centrosomes, but centrioles and spermatid basal bodies are short in length. bld10 mutant flies are viable but male sterile, producing immotile sperm whose axonemes are deficient in the central pair of microtubules. These results show that Drosophila Bld10 is required for centriole and axoneme assembly to confer cilium motility. INTRODUCTIONCentrioles lie at the core of centrosomes. They consist of a ninefold symmetrical array of nine triplet microtubules arranged in a cylinder. In most differentiated cell types, centrioles transform into basal bodies, membrane-embedded centrioles that template cilium and flagellum axoneme assembly. The requirement of cilia and flagella for many developmental and physiological processes, together with the growing list of human diseases that result from defects in basal bodies and cilia (Badano et al., 2006;Bisgrove and Yost, 2006;Bettencourt-Dias and Glover, 2007;Fliegauf et al., 2007;Marshall, 2008), drives the need to understand the basic processes involved in centriole, basal body, cilium assembly, and motility.In Drosophila several approaches have identified evolutionarily conserved centriole proteins required for centriole biogenesis including Sak, Sas4, Sas6, Ana1, Ana2, and Asterless (Bettencourt-Dias et al., 2005;Basto et al., 2006;Goshima et al., 2007;Rodrigues-Martins et al., 2007;Blachon et al., 2008). In flies, mutations in these genes abolish centrosome and cilium/flagellum assembly (except mutations in ana1 and ana2, which have not been described yet). Additional centriole/ basal body proteins including Spd-2, Drosophila pericentrin-like protein (D-PLP)/CP309, and uncoordinated (UNC) function in pericentriolar material (PCM) recruitment to centrosomes and/or the assembly of cilia and flagella Kawaguchi and Zheng, 2004;Martinez-Campos et al., 2004;Dix and Raff, 2007;Giansanti et al., 2008). Identification of the complete set of centriole components is necessary to define their individual and cooperative roles in the assembly and function of centrioles and cilia.In Chlamydomonas reinhardtii, mutations in the bld10 gene result in complete loss of flagella, giving the cells a "bald" appearance, due to a failure to assemble centrioles (Matsuura et al., 2004;Hiraki et al., 2007). Bld10p functions in the formation of the cartwheel, a ninefold symmetrical scaffold structure essential for an early step of centriole/basal body assembly . From RNA interference (RNAi) studies in cell culture, the human ort...

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Section: The Role Of Bld10 In the Assembly Of The Central Apparatus Omentioning

confidence: 87%

DrosophilaBld10 Is a Centriolar Protein That Regulates Centriole, Basal Body, and Motile Cilium Assembly

Mottier-Pavie

Megraw

2009

MBoC

107

View full text Add to dashboard Cite

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“…This animal model may be especially useful in studying the role of FMRP during embryonic development (van 't Padje et al, 2005). Many of the phenotypes uncovered from studies in Drosophila mirror human symptoms of fragile X. Macro-orchidism, alterations in locomotor activity, and changes in synapse structure are fragile X phenotypes shared among mouse, human, and Drosophila (Bakker, 1994;Comery et al, 1997;Greenough et al, 2001;Zhang et al, 2001Zhang et al, , 2004Kooy, 2003). Although severe locomotor defects (Zhang et al, 2001) may hinder the assessment of learning and memory deficits in Drosophila models (Zhang and Broadie, 2005), studies have reported alterations in the morphology of learning and memoryrelated mushroom bodies and in courtship behavior (Michel et al, 2004;McBride et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome

Zhao¹,

Toyoda²,

Ko³

et al. 2005

J. Neurosci.

267

272

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Trace fear memory requires the activity of the anterior cingulate cortex (ACC) and is sensitive to attention-distracting stimuli. Fragile X syndrome is the most common form of mental retardation with many patients exhibiting attention deficits. Previous studies in fragile X mental retardation 1 (FMR1) knock-out (KO) mice, a mouse model for fragile X, focused mainly on hippocampal-dependent plasticity and spatial memory. We demonstrate that FMR1 knock-out mice show a defect in trace fear memory without changes in locomotion, anxiety, and pain sensitivity. Whole-cell path-clamp recordings in the ACC show that long-term potentiation (LTP) was completely abolished. A similar decrease in LTP was found in the lateral amygdala, another structure implicated in fear memory. No significant changes were found in basal synaptic transmission. This suggests that synaptic plasticity in the ACC and amygdala of FMR1 KO mice plays an important role in the expression of behavioral phenotypes similar to the symptoms of fragile X syndrome.

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“…Both mouse and Drosophila disease models are similarly characterized by enlarged testes and reduced testicular function (Slegtenhorst-Eegdeman et al, 1998;Zhang et al, 2004). dfmr1 null males exhibit severely reduced fertility owing to immotile sperm .…”

Section: Dmmbiologistsorg 476mentioning

confidence: 99%

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

Coffee

Tessier

Woodruff

et al. 2010

Disease Models &Amp; Mechanisms

Self Cite

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SUMMARYFragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity.Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

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The Drosophila fragile X-related gene regulates axoneme differentiation during spermatogenesis

Cited by 68 publications

References 55 publications

DrosophilaBld10 Is a Centriolar Protein That Regulates Centriole, Basal Body, and Motile Cilium Assembly

DrosophilaBld10 Is a Centriolar Protein That Regulates Centriole, Basal Body, and Motile Cilium Assembly

Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

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