title: Age-regulated function of autophagy in the mouse inner ear.
abstract: Autophagy is a highly conserved catabolic process essential for embryonic development and adult homeostasis. The autophagic machinery supplies energy by recycling intracellular components and facilitates the removal of apoptotic cells. In the inner ear, autophagy has been reported to play roles during early development in the chicken embryo and in the response to otic injury in the adult mouse. However, there are no studies on the expression of the autophagy machinery in the postnatal and adult inner ear. Insulin-like growth factor 1 (IGF-1) is one of the factors that regulate both otic development and cochlear postnatal maturation and function. Here, we hypothesised that autophagy could be one of the processes involved in the cochlear development and functional maturation. We report that autophagy-related genes (ATG) Becn1, Atg4g and Atg5 are expressed in the mouse cochlea, vestibular system and brainstem cochlear nuclei from late developmental stages to adulthood. Atg9 was studied in the mouse cochlea and showed a similar pattern. The presence of autophagic flux was confirmed by decreased sequestosome 1 (SQSTM1/p62) and increased relative levels of microtubule-associated protein light chain 3-II (LC3-II). Inner ear autophagy flux is developmentally regulated and is lower at perinatal stages than in the adult mouse, where an expression plateau is reached at the age of two-months, coinciding with the age at which full functional activity is reached. Expression is maintained in adult mice and declines after the age of twelve months. LC3B labelling showed that autophagy was primarily associated with spiral ganglion neurons. Over time, Igf1 wild type mice showed lower expression of genes coding for IGF-1 high affinity receptor and the family factor IGF-2 than null mice. Parallel analysis of autophagy machinery gene expression showed no significant differences between the genotypes over the lifespan of the null mice. Taken together, these results show that the autophagy machinery expression in the inner ear is regulated with age but is not compromised by the chronic absence of IGF-1. Our data also strongly support that the up-regulation of autophagy machinery genes is concomitant with the functional maturation of the inner ear.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Madrid, Spain; CIBERER, Unit 761, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: de Iriarte Rodríguez
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Pulido
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Madrid, Spain; CIBERER, Unit 761, Instituto de Salud Carlos III, Madrid, Spain; IdiPAZ, Instituto de Investigación Sanitaria, Madrid, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Rodríguez-de la Rosa
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Madrid, Spain; CIBERER, Unit 761, Instituto de Salud Carlos III, Madrid, Spain; Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: mmagarinos@iib.uam.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Magariños
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, Madrid, Spain; CIBERER, Unit 761, Instituto de Salud Carlos III, Madrid, Spain; IdiPAZ, Instituto de Investigación Sanitaria, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Varela-Nieto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D003051:Cochlea / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006360:Heat-Shock Proteins / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D013136:Spiral Ganglion / Q000378:metabolism; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D006360:Heat-Shock Proteins; C513121:IGF2 protein, mouse; C561967:Ins2 protein, mouse; D007328:Insulin; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D007335:Insulin-Like Growth Factor II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017526:Receptor, IGF Type 1
keywords: ATG; Ageing; Beclin 1; Cochlea; IGF1R; Otic development; Vestibule