The quest for restoring hearing: Understanding ear development more completely

Abstract

Neurosensory hearing loss is a growing problem of super-aged societies. Cochlear implants can restore some hearing, but rebuilding a lost hearing organ would be superior. Research has discovered many cellular and molecular steps to develop a hearing organ but translating those insights into hearing organ restoration remains unclear. We cannot make various hair cell types and arrange them into their specific patterns surrounded by the right type of supporting cells in the right numbers. Our overview of the topologically highly organized and functionally diversified cellular mosaic of the mammalian hearing organ highlights what is known and unknown about its development. Following this analysis, we suggest critical steps to guide future attempts toward restoration of a functional OC. We argue that generating mutant mouse lines that mimic human pathology to fine-tune attempts toward long-term functional restoration are needed to go beyond the hope generated by restoring single hair cells.

Gene, cell, and organ multiplication drives inner ear evolution

“…Consistent with such a role for Neurod1 is that loss of Neurod1 results in continued expression of an otherwise transient Atoh1 expression in sensory neurons and their transdifferentiation into intraganglionic hair cells (Jahan et al, 2010b). Such a potential negative feedback loop was also found in hair cells that show a premature and more profound expression of Atoh1 in the apex of Neurod1 CKO mice, resulting in a partial conversion of hair cell types as a consequence of premature and elevated expression of Atoh1 (Jahan et al, 2015a; Jahan et al, 2010b, 2013). To formally test a more direct interaction between Atoh1 and Neurog1 required replacement of Atoh1 by Neurog1.…”

“…The mechanosensory cell specializations to allow sensory cells to develop this exquisite mechanosensation require a number of factors for their normal development such as the basic Helix-Loop-Helix transcription factors Atoh1 (Jahan et al, 2015b; Pan et al, 2012a) or Neurod1 (Jahan et al, 2015a) that is tightly regulated in addition through several other transcription factors such as Pou4f3 (Ikeda et al, 2015; Xiang et al, 2003). Gfi1 (Hertzano et al, 2004) and Barlh1 (Chellappa et al, 2008) to name a few.…”

“…Furthermore, the changing taxonomic positions of basal sarcopterygians necessitating to invoke a loss of this sensory patch in lungfish (assuming the sensory organ in Latimeria is ancestral to the same named organ in tetrapods), or the sensory epithelium in Latimeria being a convergent evolution associated with an equally convergent evolution of a lagena and a lagenar recess (Fritzsch et al, 2013). A second area of contention is the structural dissimilarity of the organ of Corti of all therians (Jahan et al, 2015a) and its evolution already in monotremes in terms of inner and outer hair cells (Chen and Anderson, 1985; Ladhams and Pickles, 1996) and their prestin motor (Okoruwa et al, 2008) separated by pillar cells with unusual molecular and structural features not found in other supporting cell type of any vertebrate (Jahan et al, 2015a). Importantly, in monotremes, the basilar papilla/organ of Corti resides in the lagena recess that has a lagena sensory epithelium at its tip that is entirely separated from the sound conducting perilymphatic space connected to the round and oval window (Schultz et al, 2016).…”

“…The organ of Corti is the most sophisticatedly patterned sensory organ with a highly conserved and extremely stable cellular organization in all eutherian mammals (Jahan et al, 2015a). It evolved out of a less organized organ found in monotremes through reorganization of already specified inner and outer hair cells as a consequence of coiling related elongation that rearranged multiple rows of inner and outer hair cells of monotremes (Fritzsch et al, 2013; Schultz et al, 2016) into the single row of inner and three rows of outer hair cells of eutherian mammals (Lewis et al, 1985).…”

Sensing External and Self-Motion with Hair Cells: A Comparison of the Lateral Line and Vestibular Systems from a Developmental and Evolutionary Perspective

“…This lineage relation would allow cell fate switching between afferent neurons and hair cells, given their common precursor. Indeed, loss of hair cells [Ma et al 2000; Matei et al 2005], cross-regulation of Atoh1 and Neurog1 [Raft and Groves 2015], development of intra- ganglionic hair cells when Neurod1 is removed [Jahan et al 2015c] and the ability of Neurog1 to govern some aspects of hair cell development [Jahan et al 2015b] support the notion of a molecular overlap in inner ear hair cell and sensory neuron lineages [Fritzsch et al 2010]. What remains still unclear is at which stage of placode evolution these lineages diverged.…”