Embryonic Development: The evolution of hearing and balance
New genetic tools have allowed researchers to compare how the brainstem auditory and vestibular nuclei develop in embryonic chicks and mice.
- University of California, Irvine, United States
The ear is an organ with two main roles – hearing and balance – and it relies on mechanically sensitive hair cells to perform both jobs. When the ear detects a sound, it sends signals to clusters of neurons called the brainstem auditory nuclei, and when it registers movement of the head, it sends signals to the brainstem vestibular nuclei. The vestibular nuclei are remarkably similar among vertebrates, from fish to humans (Fritzsch et al., 2014). However, the auditory nuclei display considerable diversity across species. For example, birds and mammals both have a pathway that uses the difference in the time of arrival of a sound at each ear to determine where the noise came from. However, this circuit works differently in these two groups of animals, suggesting that it may have emerged independently multiple times during evolution (Grothe and Pecka, 2014). How, then, did the modern auditory and vestibular nuclei arise?
One strategy to address this question is to explore the embryonic development of vertebrates. Nuclei in the brainstem arise from the embryonic hindbrain, which is remarkably similar across vertebrate species and is divided into segments called rhombomeres (Di Bonito and Studer, 2017). Fate mapping studies have been used to test whether cells in the auditory and vestibular nuclei of different vertebrate species derive from the same rhombomeres.
In this technique, embryonic tissue can be labeled with an external marker, such as a dye (for traditional fate mapping), or a fluorescent protein marker (for genetic fate mapping), in order to track the destination of the cells arising from that tissue (Stern and Fraser, 2001; Legué and Joyner, 2010). Previously, traditional fate mapping has been limited to research in birds (which have accessible embryos), while genetic fate mapping has been limited to mammals (which have accessible genomes; Cramer et al., 2000; Marín and Puelles, 1995; Kim and Dymecki, 2009).
However, both approaches have technical caveats and they identify progenitors in different ways, which hinders their direct comparison. Traditional fate mapping identifies the fate of all labeled cells within a restricted area of the embryo, which may contain a range of progenitor cell types. In contrast, genetic fate mapping marks only cells that express a certain gene (or genes), but these cells can come from a wider area within the embryo.
Now, in eLife, Marcela Lipovsek and Richard Wingate of King’s College London report how they have addressed this dilemma by using vector-based genetic fate mapping in chick embryos (Lipovsek and Wingate, 2018). The researchers focused on genes that were only active in certain regions of the embryonic hindbrain. Plasmid vectors were used to label cells with a fluorescent protein after specific genes in those cells were active. This way, the fate of cells along two anatomical axes (from head to tail, and from back to belly) could be traced. Lipovsek and Wingate studied the same genes that were previously used to construct genetic fate maps of brainstem nuclei in mice, which enabled them to draw direct comparisons between birds and mammals for the first time (Di Bonito and Studer, 2017).
Their results confirmed that vestibular nuclei have similar embryonic origins in chicks and mice. In contrast, auditory nuclei that have comparable roles in chicks and mice arise from completely different embryonic tissues. This suggests that birds and mammals used different populations of ancestral cells – often from different rhombomeres – to independently evolve circuits for calculating sound location.
Lipovsek and Wingate provide compelling evidence that the anatomical similarities between vestibular nuclei in birds and mammals are due to common developmental and evolutionary origins. And since their vestibular systems are also homologous to those of fish, it seems that the role of the vestibular organ remained relatively unaffected by our aquatic ancestors’ move to land (Fritzsch et al., 2014). Conversely, the different developmental origins of auditory nuclei in birds and mammals reflect how each clade solved the problem of hearing on land by adapting to its own ecological niche (Carr and Christensen-Dalsgaard, 2016).
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Forrest P Weghorst
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© 2019, Weghorst and Cramer
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Embryonic Development: The evolution of hearing and balance
eLife 8:e44567.
https://doi.org/10.7554/eLife.44567
Further reading
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- Developmental Biology
- Neuroscience
Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered – swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.
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- Developmental Biology
The spatial and temporal linear expression of Hox genes establishes a regional Hox code, which is crucial for the antero-posterior (A-P) patterning, segmentation, and neuronal circuit development of the hindbrain. RNF220, an E3 ubiquitin ligase, is widely involved in neural development via targeting of multiple substrates. Here, we found that the expression of Hox genes in the pons was markedly up-regulated at the late developmental stage (post-embryonic day E15.5) in Rnf220-/- and Rnf220+/- mouse embryos. Single-nucleus RNA sequencing (RNA-seq) analysis revealed different Hox de-repression profiles in different groups of neurons, including the pontine nuclei (PN). The Hox pattern was disrupted and the neural circuits were affected in the PN of Rnf220+/- mice. We showed that this phenomenon was mediated by WDR5, a key component of the TrxG complex, which can be polyubiquitinated and degraded by RNF220. Intrauterine injection of WDR5 inhibitor (WDR5-IN-4) and genetic ablation of Wdr5 in Rnf220+/- mice largely recovered the de-repressed Hox expression pattern in the hindbrain. In P19 embryonal carcinoma cells, the retinoic acid-induced Hox expression was further stimulated by Rnf220 knockdown, which can also be rescued by Wdr5 knockdown. In short, our data suggest a new role of RNF220/WDR5 in Hox pattern maintenance and pons development in mice.
