Trks and p75 genes are differentially expressed in the inner ear of human embryos. What may Trks and p75 null mutant mice suggest on human development?

Recent work has shown the expression of Neurotrophins low (p75) and high affinity (Trk's A, B, and C) receptors in the developing inner ear sensory neurons of chick and mouse. Likewise the biological significance of such receptor expression was demonstrated by using both Trks and Neurotrophins null mutant mice. The present study was conducted to determine the expression of Trks and p75 proteins in the human inner ear throughout development. Hence to assess the potential role of Neurotrophins in the development of auditory and vestibular specific innervation in man. In other words, we intend to address the issue whether or not what null mutant mice for Trks and p75 have revealed on inner ear development may be relevant for human embryos. Fifty-two inner ears and their cochleovestibular ganglions (CVG) from human embryos and fetuses, ranging from 5 to 24 weeks of pregnancy were analyzed. Both Western blot and immunocytochemistry on frozen sections were used as complementary procedures. Quantitative Western blot studies revealed that Trk-B and C immunoreactivity (IR) appeared by embryonic week 5 in CVG neurons, increased at high levels between embryonic weeks 7 and 12, and later on, in 15 week-old specimens and older began to decrease to minimal levels. Trk-A IR was detected at just moderate levels during 5 and 7 weeks reflecting the presence of NGF high affinity receptors only at these earlier developmental ages. The p75 IR was detected at high degrees in the early stage of the 5th week and at abundant levels in all studied inner ears from the 7th to the 24th pregnancy week. These Western blot observations were corroborated by immunocytochemistry on frozen sections, which also revealed a major distribution of both p75 and Trks on neuronal bodies while p75 appears localized on supporting cells. Our findings reveal a tight correlation between p75 and Trks expression throughout human development and specific inner ear developmental events, such as target-dependent neuronal cell death and afferent hair cells innervation. That kind of association of p75 and Trks temporal pattern with distinctive steps in inner ear developmental schedule, is a feature shared between human embryos and other mammals, such as mouse. Based on the present results and considering them together with the reported phenotype of p75 and Trks null mutant mice, we hypothesize that p75 and Trk receptors, as well as, their binding Neurotrophins may be essential in human inner ear development. Accordingly, they may be required molecules for sensory epitheliums innervation and target-dependent neuronal cell death, during embryogenesis and even early postnatal life, in man.