Abstract
Sphingolipids are bioactive lipid components of cell membranes with important signal transduction functions in health and disease. Ceramide is the central building block for sphingolipid biosynthesis and is processed to form structurally and functionally distinct sphingolipids. Ceramide can be phosphorylated by ceramide kinase (CERK) to generate ceramide-1-phosphate, a cytoprotective signaling molecule that has been widely studied in multiple tissues and organs, including the developing otocyst. However, little is known about ceramide kinase regulation during inner ear development. Using chicken otocysts, we show that genes for CERK and other enzymes of ceramide metabolism are expressed during the early stages of inner ear development and that CERK is developmentally regulated at the otic vesicle stage. To explore its role in inner ear morphogenesis, we blocked CERK activity in organotypic cultures of otic vesicles with a specific inhibitor. Inhibition of CERK activity impaired proliferation and promoted apoptosis of epithelial otic progenitors. CERK inhibition also compromised neurogenesis of the acoustic-vestibular ganglion. Insulin-like growth factor-1 (IGF-1) is a key factor for proliferation, survival and differentiation in the chicken otocyst. CERK inhibition decreased IGF-1-induced AKT phosphorylation and blocked IGF-1-induced cell survival. Overall, our data suggest that CERK is activated as a central element in the network of anti-apoptotic pro-survival pathways elicited by IGF-1 during early inner ear development.
Highlights
The vertebrate inner ear contains the organs responsible for the perception of sound and balance whose functions are mediated by specialized mechanoreceptor cells maintained in position by support cells and innervated by the terminations of the auditory and vestibular ganglia (Magariños et al, 2012)
We found that inhibition of ceramide kinase (CERK) activity in otic vesicle cultures decreased otic vesicle size and reduced progenitor cell proliferation, and this was accompanied by elevated cell cycle arrest and apoptosis, and compromised acoustic-vestibular ganglion (AVG) neurogenesis, demonstrating that CERK is essential for otocyst development and AVG neurogenesis
Genes Encoding the Main Ceramide Metabolism Enzymes and for Insulin-like growth factor-1 (IGF-1) Are Expressed in the Developing Chicken Inner Ear
Summary
The vertebrate inner ear contains the organs responsible for the perception of sound and balance whose functions are mediated by specialized mechanoreceptor cells maintained in position by support cells and innervated by the terminations of the auditory and vestibular ganglia (Magariños et al, 2012). Ceramide Kinase in Otic Cultures of great prevalence in the case of deafness (WHO: 1 in 4 people projected to have hearing problems by 2050, WHO, 2021). As these postmitotic sensory cells do not regenerate in mammals, but do so birds, there is great interest in understanding the molecular and genetic bases of the formation of these highly differentiated cells during development, including in experimental bird models (Shi and Edge, 2013; Roccio et al, 2019). The transition from otic progenitors to mature inner ear cells occurs through the spatiotemporal regulation of proliferation, differentiation, migration, apoptosis, senescence, and autophagic processes, which creates the highly organized architecture of the adult sensory organ (Sánchez-Calderón et al, 2007; Varela-Nieto et al, 2019). The otic epithelium is a source of neural progenitors, the ventromedial region from where neural progenitors delaminate and migrate to form the neurons of the acoustic-vestibular ganglion (AVG) (D’Amico-Martel, 1982; Bell et al, 2008)
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