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The Drosophila Junctophilin Gene Is Functionally Equivalent to Its Four

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The Drosophila Junctophilin Gene Is Functionally Equivalent to Its Four © 2018. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2018) 11, dmm029082. doi:10.1242/dmm.029082 RESEARCH ARTICLE The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway Eduardo Calpena1,*, Vıctoŕ López del Amo1, Mouli Chakraborty2,3, Beatriz Llamusı2,3́ , Rubén Artero2,3, Carmen Espinós1,4,‡ and Máximo I. Galindo1,4,5,‡,§ ABSTRACT KEY WORDS: Junctophilin, Drosophila, Cardiomyopathy, Huntington’s disease, Notch Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members INTRODUCTION (JPH1-JPH4) that are differentially expressed throughout excitable cells. Junctophilin (JPH) family proteins contribute to the formation and The analysis of knockout mice lacking JPH subtypes has demonstrated maintenance of junctional membrane complexes (JMCs) by serving their essential contribution to physiological functions in skeletal and as a physical bridge between the plasma membrane (PM) and the cardiac muscles and in neurons. Moreover, mutations in the human endoplasmic reticulum (ER) membrane in excitable cells, allowing JPH2 gene are associated with hypertrophic and dilated the functional crosstalk between ion channels (Takeshima et al., cardiomyopathies; mutations in JPH3 are responsible for the 2015, 2000). Silencing or genetic ablation of the JPH genes 2+ neurodegenerative Huntington’s disease-like-2 (HDL2), whereas JPH1 produces defects in Ca homeostasis (Hirata et al., 2006; Ito et al., acts as a genetic modifier in Charcot–Marie–Tooth 2K peripheral 2001; Li et al., 2010; Moriguchi et al., 2006; Takeshima et al., 2015, neuropathy. Drosophila melanogaster has a single junctophilin ( jp) 2000). In mammals, this family comprises four members (JPH1- gene, as is the case in all invertebrates, which might retain equivalent JPH4) that are differentially expressed: JPH1 is predominantly functions of the four homologous JPH genes present in mammalian expressed in skeletal muscle, JPH2 in skeletal muscle and heart, and genomes. Therefore, owing to the lack of putatively redundant genes, a JPH3 and JPH4 genes are coexpressed in neural tissues (Nishi et al., jp Drosophila model could provide an excellent platform to model the 2000, 2003; Takeshima et al., 2000). Junctophilin-related diseases, to discover the ancestral functions of the Jph1 knockout (KO) mice exhibit suckling failure and die shortly JPH proteins and to reveal new pathways. By up- and downregulation of after birth with morphological and physiological abnormalities in Jp in a tissue-specific manner in Drosophila, we show that altering its skeletal muscle, including fewer JMCs, failure of normal triad levels of expression produces a phenotypic spectrum characterized by development, abnormal ER features and reduced contractile force muscular deficits, dilated cardiomyopathy and neuronal alterations. (Ito et al., 2001; Komazaki et al., 2002). Jph2 plays a key role in Importantly, our study has demonstrated that Jp modifies the neuronal cardiomyocyte development and stability of myocyte ultrastructure degeneration in a Drosophila model of Huntington’s disease, and it has (Beavers et al., 2014; Chen et al., 2013; Reynolds et al., 2013; allowed us to uncover an unsuspected functional relationship with the Takeshima et al., 2000). Jph2 null mice die during the early embryonic Notch pathway. Therefore, this Drosophila model has revealed new development, as a result of cardiac failure (Takeshima et al., 2000). aspects of Junctophilin function that can be relevant for the disease Cardiac myocytes from these mutant mice showed deficiency of the mechanisms of their human counterparts. JMCs and abnormal structures in ER and mitochondria. Mice with decreased levels of cardiac Jph2 showed defective postnatal T-tubule maturation, whereas mice overexpressing Jph2 had accelerated 1Program in Molecular Mechanisms of Disease, Centro de InvestigaciónPrıncipé T-tubule maturation (Reynolds et al., 2013). Inducible cardiac- Felipe (CIPF), c/ Eduardo Primo Yúfera no. 3, 46012 Valencia, Spain. 2Translational specific Jph2 knockdown in mice leads to ventricular dilatation, Genomics Group, Incliva Health Research Institute, Avda. Menendez Pelayo 4 acc 46010, Valencia, Spain. 3Department of Genetics and Estructura de Recerca postnatal heart failure and increased mortality (Reynolds et al., 2013). Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de Jph3 null mice exhibit adult onset, progressive motor Valencia,̀ c/ Dr Moliner 50, 46100 Burjasot, Spain. 4UPV-CIPF Joint Unit Disease dysfunction, whereas Jph3 hemizygous mice have a similar but Mechanisms and Nanomedicine, 46012 Valencia, Spain. 5Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo milder phenotype (Seixas et al., 2012). Knockout mice lacking Jph4 Tecnológico (IDM), Universitat Politecnicà de Valencia,̀ Universitat de Valencia,̀ show no obvious abnormalities, suggesting functional redundancy 46022 Valencia, Spain. *Present address: Clinical Genetics Group, Weatherall Institute of Molecular between Jph3 and Jph4 (Moriguchi et al., 2006). Double KO mice Medicine, University of Oxford, Oxford OX3 9DS, UK. lacking both Jph3 and Jph4 genes have severe growth retardation ‡These authors contributed equally to this work and die within 3-4 weeks after birth, probably as a result of §Author for correspondence ([email protected]) impairment of the neuronal circuit controlling the salivary gland (Moriguchi et al., 2006). In addition, they exhibit impaired motor B.L., 0000-0002-2694-1293; R.A., 0000-0003-1596-047X; C.E., 0000-0003- coordination, learning and memory (Ikeda et al., 2007; Kakizawa 4435-1809; M.I.G., 0000-0001-8448-9760 et al., 2008; Moriguchi et al., 2006). This is an Open Access article distributed under the terms of the Creative Commons Attribution JPH genes have been found to play important roles in pathology. License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. In an mdx mouse model of Duchenne muscular dystrophy, aberrant Jph1 proteolysis was detected, providing an association with the Received 23 December 2016; Accepted 8 November 2017 development of primary muscle disease (Murphy et al., 2013). JPH2 Disease Models & Mechanisms 1 RESEARCH ARTICLE Disease Models & Mechanisms (2018) 11, dmm029082. doi:10.1242/dmm.029082 dysregulation has been associated with variety of heart diseases for a 129-amino acid-long open reading frame, is probably spurious (Landstrom et al., 2014; Takeshima et al., 2015). Decreased levels and definitely nonfunctional, because it lacks most functional of Jph2 expression have been reported in animal models of domains. To generate a UAS-jp, we obtained a stock with an aortic stenosis (Xu et al., 2007) and hypertrophic and dilated insertion of the P{XP} transgene within the jp locus, P{XP}jpd04563. cardiomyopathy (Minamisawa et al., 2004). In addition, in human This P{XP} transgenic construct is inserted upstream of the first failing heart samples or in patients with hypertrophic coding exon (Fig. 1A) and has two UAS promoters, one at each end cardiomyopathy, the JPH2 levels are markedly reduced and in different orientations, so that the right promoter points (Landstrom et al., 2011; Zhang et al., 2013). Importantly, towards the jp gene and the left promoter towards the upstream dominant mutations in the human JPH2 gene are associated with region (Thibault et al., 2004). This second promoter is flanked by hypertrophic and dilated cardiomyopathy (Beavers et al., 2013; FRT recombination sites, so it was removed by crossing to an FLP Landstrom et al., 2007; Sabater-Molina et al., 2016) and constitute a transgene, leaving only the jp-specific UAS promoter. Details of relatively rare cause of congenital cardiomyopathies. this process are given in Fig. S1. This insertion will be referred to as Huntington’s disease-like 2 (HDL2) is a rare, autosomal UAS-jp. An advantage of this UAS line compared with the ones dominant neurodegenerative disorder that is clinically almost generated by random insertion is that, as it is already inserted in the indistinguishable from Huntington’s disease (HD). HDL2 is target locus, it does not produce insertional mutations in other caused by a CTG/CAG expansion located within the alternatively genes. As the insertion is viable in homozygosis, most probably it spliced exon 2A of the JPH3 gene (Holmes et al., 2001). The does not affect expression of the jp gene substantially, but we cannot pathogenicity of this mutation involves both a toxic gain of function discard the possibility that it partly hinders expression and therefore attributable to the expansion and a reduction in the levels of JPH3 it could be a mild hypomorphic allele. In order to test this protein expression (Seixas et al., 2012). Recently, JPH1 has been possibility, we quantified the jp mRNA levels in individuals described as a genetic modifier for the Charcot–Marie–Tooth 2K heterozygous and homozygous for the insertion. This analysis (CMT2K) peripheral neuropathy (Pla-Martin et al., 2015). revealed no statistically significant differences with Oregon-R wild- Drosophila melanogaster has a single junctophilin ( jp) gene, as type flies (Fig. 1B); thus, the insertion
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