Insulin-Like Growth Factor Signaling Regulates the Timing of Sensory Cell Differentiation in the Mouse Cochlea

Abstract

The mammalian auditory sensory epithelium, the organ of Corti, is a highly ordered cellular structure that comprises two types of auditory hair cells and several types of nonsensory supporting cells. During embryogenesis, a stereotyped sequence of cellular and molecular events is required for its development. These processes are assumed to be regulated by multiple growth and transcription factors. However, the majority of these factors have not been identified. One potential regulator of cochlear development is the insulinlike growth factor (IGF) signaling family. To examine the roles of the IGF pathway in inner ear formation, cochleae from Igf1r mutant mice were analyzed. Deletion of Igf1r leads to several changes in inner ear development including a shortened cochlear duct, a decrease in the total number of cochlear hair cells, and defects in the formation of the semicircular canals. In addition, maturation of the cochlear sensory epithelium was delayed at the transition point between cellular proliferation and differentiation. To determine the molecular basis for these defects, inhibition of IGF signaling was replicated pharmacologically in vitro. Results indicated that IGF signaling regulates cochlear length and hair cell number as well as Atoh1 expression through the phosphatidylinositol 3-kinase/Akt signaling pathway. These results demonstrate novel roles for IGF signaling in inner ear development including regulation of vestibular formation, length of the cochlear duct, and the number of cochlear hair cells. The results also provide new insights regarding the pathological processes that underlie auditory defects in the absence of IGF signaling in both humans and mice.

Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice

“…Finally, a group of organs, including kidney, spleen and cochlea, did not show evident histological alterations, which would support a less crucial IGF1R functional implication in these organs. However, it is well known that inner ear development is highly dependent on IGF signaling, mainly during postnatal cochlear maturation (Camarero et al 2001;Okano et al 2011). It would be of interest to analyze the cochlea of UBC-CreERT2; Igf1r fl/fl mutants at later developmental stages to see if decreased levels of IGF1R predispose mice to hearingloss with aging, as previously stated (Riquelme et al 2010).…”

“…Classical Igf1r-deficient (IGF1R knockout) mice die at birth presumably due to respiratory failure and exhibit a 55 % decrease in body weight compared to wild type controls. Prenatal IGF1R knockout embryos exhibit growth retardation and generalized developmental abnormalities, comprising hypoplasia, altered central nervous system, abnormal skin formation, delayed bone development, reduced pancreatic beta-cells, failure of testicular determination, lung immaturity and cochlear defects (Bonnette and Hadsell 2001;Epaud et al 2012;Liu et al 1993;Nef et al 2003;Okano et al 2011;Scolnick et al 2008;Withers et al 1999).…”

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

“…LIN28B has been shown to positively regulate Igf1r-PI3K/Akt pathway (27); however, loss of Igfr1 within the developing cochlea does not mirror LIN28B's effects on HC differentiation. In the Igfr1 mutant cochlea, prosensory cell cycle exit occurs prematurely while HC differentiation is delayed (73). Functional connections between the Shh signaling pathway and LIN28B have not yet been established; however, the tools described here will allow future examination of this link.…”

“…How might LIN28B alter the timing of HC differentiation? To date two pathways, the Insulin-like growth factor (Igfr1)-phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the Shh pathway, have been shown to influence timing of HC differentiation within the murine cochlea (65)(66)(67)73). LIN28B has been shown to positively regulate Igf1r-PI3K/Akt pathway (27); however, loss of Igfr1 within the developing cochlea does not mirror LIN28B's effects on HC differentiation.…”

In Vitro Differentiation of Human Bone Marrow Mesenchymal Stem Cells to Hair Cells Using Growth Factors

“…The use of growth factors to differentiate stem cells to the hair cells is important. In natural development, the signaling of growth factors is very essential to the development of the inner ear 25 .…”