G.P.14

Facio Scapulo Humeral Dystrophy (FSHD) is a muscle disease that asymmetrically affects flat muscles. Non-muscle symptoms are deafness and retinopathies. Defects very evocative of FSHD have been observed in mouse model partially deficient for FAT1. In addition, genetic screening of neuromuscular disease patients enabled us to identify the FAT1 mutations in FSHD-like patients. The family of FAT protocadherins (FAT 1–4) is well known to be involved in the Wnt/PCP and in the Hippo pathway in Drosophila, while it plays key roles in homeostasis of mammalian tissues. FAT1 expression is localized in developing limb buds, somites and neural tube as well as in adult kidney. Based on these data and on our previous results, we postulated that FAT1 plays a role in generation and homeostasis of flat muscle tissues. To understand which proteins compose the transduction pathway led by FAT1 in mammals, we first looked at the stability and activation of YAP transcription factor in the Hippo pathway. Although preliminary, results confirmed that FAT1 overexpression affects YAP/TAZ phosphorylation, nuclear localization and transcriptional activity, which may stop cell proliferation and affect cell polarity. Indeed, localization of YAP/TAZ depends from elasticity of the cellular environment through signal transduction from the extracellular matrix (ECM). In mesenchymal stem cells, TAZ and YAP are cytoplasmic when cells are on flexible substrates while nuclear on rigid matrices. Therefore, we plan to test muscle cells reaction to different levels of matrix rigidity and to measure functional consequences of FAT1 alterations to these mechanical stresses. In perspective, our observations will help explain the molecular mechanism involved in the differentiation and tissue response to cellular environment. Moreover, FAT1 alteration may lead to modification of ECM stiffness perception during flat muscle fibers development, thus contributing to pathological mechanism of FSHD. Facio Scapulo Humeral Dystrophy (FSHD) is a muscle disease that asymmetrically affects flat muscles. Non-muscle symptoms are deafness and retinopathies. Defects very evocative of FSHD have been observed in mouse model partially deficient for FAT1. In addition, genetic screening of neuromuscular disease patients enabled us to identify the FAT1 mutations in FSHD-like patients. The family of FAT protocadherins (FAT 1–4) is well known to be involved in the Wnt/PCP and in the Hippo pathway in Drosophila, while it plays key roles in homeostasis of mammalian tissues. FAT1 expression is localized in developing limb buds, somites and neural tube as well as in adult kidney. Based on these data and on our previous results, we postulated that FAT1 plays a role in generation and homeostasis of flat muscle tissues. To understand which proteins compose the transduction pathway led by FAT1 in mammals, we first looked at the stability and activation of YAP transcription factor in the Hippo pathway. Although preliminary, results confirmed that FAT1 overexpression affects YAP/TAZ phosphorylation, nuclear localization and transcriptional activity, which may stop cell proliferation and affect cell polarity. Indeed, localization of YAP/TAZ depends from elasticity of the cellular environment through signal transduction from the extracellular matrix (ECM). In mesenchymal stem cells, TAZ and YAP are cytoplasmic when cells are on flexible substrates while nuclear on rigid matrices. Therefore, we plan to test muscle cells reaction to different levels of matrix rigidity and to measure functional consequences of FAT1 alterations to these mechanical stresses. In perspective, our observations will help explain the molecular mechanism involved in the differentiation and tissue response to cellular environment. Moreover, FAT1 alteration may lead to modification of ECM stiffness perception during flat muscle fibers development, thus contributing to pathological mechanism of FSHD.