Animal Models of Speech and Language Disorders by Santosh A. Helekar

Author:Santosh A. Helekar
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

Conclusion

Exosomal WNT Signaling May Be Critical in Learned Vocalization

We have provided what we think is a singularly explanatory dissection of molecular and genetic contributions to speech and language. The crux of our hypothesis is that birdsong, speech, and language may be especially sensitive to disturbances to synaptic Wnt signaling processes (perhaps especially Wnt5-family mediated) that occur during the production of learned sounds. The complexity of the Wnt signaling process (including exosomal secretory and uptake mechanisms) appropriately parallels the wide diversity of genetic mutations that, in humans, affect speech and language. In general terms, this has a parallel with an emerging view on the cellular and genetic mechanisms that contribute to stuttering, where mutations in genes encoding lysosomal enzymes have been implicated [462]. Songbird studies developed as a model for stuttering (see Chap.​ 7 by Helekar) have not yet advanced to the point of exploring the contribution of these genes (GNPTAB, GNPTG, NAGPA) in song production, but this represents an exciting avenue for future research. Currently, we haven’t explored mechanistic connections between the lysosomal processing pathway implicated in human genetic studies on stuttering and the synaptic Wnt/exosome-centric pathway we have posited to be involved in striatal contributions to speech. Ultimately, these cellular processes must cooperate in the production of speech, although not necessarily simultaneously in the same cells. Some evidence suggests the possibility that CNTNAP2, or genes in the vicinity, may also be involved in stuttering and/or Tourette syndrome [463–465].

Space limitations prevent us from discussing many other genes in Table 6.2 that could be of relevance to the hypothesis we have outlined here. A more useful exercise is to ask whether this WNT–exosome framework might lend additional support to genes currently implicated in speech and language deficits, provide new perspectives on their function, or unveil new candidates in loci that have been extensively researched, but for which a guilty party remains at large. A balanced translocation or deletions disrupting the C10orf11 gene at 10q22 result in psychomotor delay, with patients carrying even the smallest deletions producing only a few words by age 4 [466, 467]. Very little is known about C10orf11, except that the gene is highly conserved, potentially regulated by p63, and, based on a loss-of-function genetic screen in Ciona intestinalis (the tunicate sea squirt), encodes a novel component of the Wnt/β-catenin signaling pathway [468]. A copy number gain of C10orf11 has also been noted in a patient with autism [469]. Thus, the threads we have pulled together in this chapter might provide a context for C10orf11 functioning as a bona fide participant in speech and language production.

Several studies have identified the ankyrin repeat domain-containing protein 11 (ANKRD11) gene at 16q24.3 as involved in KBG syndrome, with typical speech delay, variable cognitive impairment, and autism-like features [470–472]. The framework advanced in this chapter provides an entrypoint to understand the mechanism of ANKRD11’s contribution to speech and cognitive function, given that the ANKRD11 protein may impinge on p53/p63 function [138, 473, 474]. Additionally, the gene encoding the frizzled-related protein, FRZB (a.k.a. secreted frizzled-related protein 3, SFRP3), falls in the critical region for 2q31.

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