INSULIN-LIKE GROWTH FACTORS AND HEARING: WHAT CAN WE LEARN FROM MICE?

Isabel Varela Nieto

Department of Animal Models of Human Diseases. Instituto de Investigaciones Biomédicas “Alberto Sols” CSIC-UAM. CIBERER Unit 761. 28029 Madrid. Spain.

Insulin-like growth factor-I (IGF-I) provides pivotal cell survival and differentiation signals during inner ear development throughout evolution. Homozygous mutations of human IGF1 cause syndromic sensorineural deafness, decreased intrauterine and postnatal growth rates, and mental retardation. In the mouse, deficits in IGF-I result in profound hearing loss associated with reduced survival, differentiation and maturation of auditory ganglion cells. Nevertheless, little is known about the molecular basis of IGF-I activity in hearing and deafness.

A combination of quantitative RT-PCR, subcellular fractionation and Western blotting, along with in situ hybridization studies show IGF-I and its high affinity receptor to be strongly expressed in the embryonic mouse cochlea. The expression of both these proteins decreases after birth and in the cochlea of E18.5 embryonic Igf1-/- null mice, the balance of the main IGF-I related signalling pathways is altered, with lower activation of Akt and ERK1/2 and stronger activation of p38 kinase. By comparing the Igf1-/- and Igf1+/+ transcriptome in E18.5 mouse cochleae, it was shown the up-regulation of the forkhead box M1 (FoxM1) transcription factor and the misexpression of the neural progenitor transcription factors Six6 and Mash1 associated with the loss of IGF-I. Parallel, in silico promoter analysis of the genes modulated in conjunction with the loss of IGF-I revealed the possible involvement of myocyte enhancing factor 2 (MEF2) in cochlear development. E18.5 Igf1+/+ mouse auditory ganglion neurons showed intense MEF2 nuclear staining, whereas in the absence of IGF-I both nuclear and cytoplasmic levels of MEF2 were diminished. By contrast, there was an increase in the nuclear accumulation of FoxM1 and a corresponding decrease in the nuclear cyclin-dependent kinase inhibitor p27Kip1.

These results reveal novel regulatory mechanisms that are at play during cochlear development and that are modulated by IGF-I in promoting sensory cell and neural survival and differentiation. These data will help better understand the molecular bases of human sensorineural deafness associated to deficits in IGF-I.

Acknowledgments. Project supported by DIGNA Biotech and SAF2008-00470.