Abstract
The intrinsic muscles of the larynx are innervated by the vagal motor nucleus ambiguus (nAmb), which provides direct motor control over vocal production in humans and rodents. Here, we demonstrate in mice using the Phox2bCre line, that conditional embryonic deletion of the gene encoding the MET receptor tyrosine kinase (MET) in the developing brainstem (cKO) results in highly penetrant, severe deficits in ultrasonic vocalization in early postnatal life. Major deficits and abnormal vocalization patterns persist into adulthood in more than 70% of mice, with the remaining recovering the ability to vocalize, reflecting heterogeneity in circuit restitution. We show that underlying the functional deficits, conditional deletion of Met results in a loss of approximately one-third of MET+ nAmb motor neurons, which begins as early as embryonic day 14.5. The loss of motor neurons is specific to the nAmb, as other brainstem motor and sensory nuclei are unaffected. In the recurrent laryngeal nerve, through which nAmb motor neurons project to innervate the larynx, there is a one-third loss of axons in cKO mice. Together, the data reveal a novel, heterogenous MET-dependence, for which MET differentially affects survival of a subset of nAmb motor neurons necessary for lifespan ultrasonic vocal capacity.
Highlights
The ability to vocalize is an essential form of communication in most vertebrates (Barkan and Zornik, 2020)
We reported previously in prenatal mice that highly restricted subsets of developing medullary neurons in the nucleus tractus solitarius (NTS) and larynx-projecting nucleus Ambiguus (nAmb) motor neurons express MET receptor tyrosine kinase (MET) (Wu and Levitt, 2013; Kamitakahara et al, 2017), positioning this receptor tyrosine kinase as a candidate for influencing the development of vocalization circuits
To test whether vagal motor output is functionally altered following loss of MET, conditional knockout (cKO) mice were used to examine ultrasonic vocalizations (USVs) evoked by a standard method of brief isolation of mouse pups from the nest recorded on postnatal day (P) 7
Summary
The ability to vocalize is an essential form of communication in most vertebrates (Barkan and Zornik, 2020). Vocalization Circuit Development Requires MET readily after birth (Hofer, 1996; Roubertoux et al, 1996; Arriaga et al, 2012; Hernandez-Miranda et al, 2017; Barkan and Zornik, 2020). Deletion of Olig or Tlx result in the loss of large portions of the nucleus tractus solitarius (NTS) and dramatic reductions in early postnatal USVs (Hernandez-Miranda et al, 2017). We reported previously in prenatal mice that highly restricted subsets of developing medullary neurons in the NTS and larynx-projecting nAmb motor neurons express MET (Wu and Levitt, 2013; Kamitakahara et al, 2017), positioning this receptor tyrosine kinase as a candidate for influencing the development of vocalization circuits
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