Shaping of inner ear sensory organs through antagonistic interactions between Notch signalling and Lmx1a

Abstract

The mechanisms of formation of the distinct sensory organs of the inner ear and the non-sensory domains that separate them are still unclear. Here, we show that several sensory patches arise by progressive segregation from a common prosensory domain in the embryonic chicken and mouse otocyst. This process is regulated by mutually antagonistic signals: Notch signalling and Lmx1a. Notch-mediated lateral induction promotes prosensory fate. Some of the early Notch-active cells, however, are normally diverted from this fate and increasing lateral induction produces misshapen or fused sensory organs in the chick. Conversely Lmx1a (or cLmx1b in the chick) allows sensory organ segregation by antagonizing lateral induction and promoting commitment to the non-sensory fate. Our findings highlight the dynamic nature of sensory patch formation and the labile character of the sensory-competent progenitors, which could have facilitated the emergence of new inner ear organs and their functional diversification in the course of evolution.

Generation of Inner Ear Sensory Neurons Using Blastocyst Complementation in a Neurog1 - Deficient Mouse

“…This unexpected nding led to the analysis of heterozygous inner ears with and without complementation, and generated data which suggests that Neurog1 is dose-dependently required for nonsensory development while largely preserving neurosensory development. This may suggest that Neurog1 is involved in a binary decision to either adopt a non-sensory or neurosensory fate through an interaction with Notch signaling, a notion consistent with previous studies (15,32,33,37). Importantly, the observed non-sensory defects in the Neurog1 +/− were rescued in successfully complemented chimeric samples (Fig.…”

A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

“…The same study suggested that Lmx1a is important in defining the non-sensory and sensory epithelium in the inner ear (Nichols et al 2008). A recent study confirms this role and shows that separation of sensory and non-sensory domains in the inner ear is regulated by mutually antagonistic signals: Notch signaling and Lmx1a (Mann et al 2017). Lmx1a regulates sensory organ segregation by antagonizing lateral induction and promoting commitment to the non-sensory fate (Mann et al 2017).…”

Hear, Hear for Notch: Control of Cell Fates in the Inner Ear by Notch Signaling

“…An interesting feature of the canonical prosensory markers, Sox2 and Jag1, and the canonical non-sensory marker Lmx1a, is that they are all expressed in a broad pattern throughout the otic cup as it closes [17,26,43]. However, as prosensory development begins, the expression of all three genes shifts and eventually separates over a 48 h period until Sox2 and Jag1 demarcate prosensory domains and Lmx1a is relegated to non-sensory epithelium [38,[44][45][46][47][48][49]. Fate mapping of Sox2 expression using a Sox2CreERT2 knock-in mouse has confirmed that the broad domain of Sox2 expressing cells present in in the early otic cup will form both future sensory and non-sensory tissues [50,51].…”

“…The solution to this paradox appears to come in the form of a non-sensory signal that opposes prosensory identity, with one of the key transcriptional effectors of this signal being Lmx1a. It has been demonstrated that Lmx1a is expressed in the non-sensory epithelium of the otocyst, with an initial stronger expression pattern on the medial side of the otocyst compared to the lateral side [26,43,49]. Loss of Lmx1a results in a deformed vestibular morphology suggestive of a failure to form semicircular canals and lack of a distinctly separated utricle and saccule, as well as enlarged vestibular sensory organs, often lacking separation between them [27,49].…”