Frameshift mutations of YPEL3 alter sensory circuit function in Drosophila

ABSTRACT A frameshift mutation in Yippee-like ( YPEL) 3 was recently found from a rare human disorder with peripheral neurological conditions including hypotonia and areflexia. The YPEL gene family is highly conserved from yeast to human, but their functions are poorly defined. Moreover, the pathogenicity of the human YPEL3 variant is completely unknown. To tackle these issues, we generated a Drosophila model of human YPEL3 variant by CRISPR-mediated In-del mutagenesis. Gene-trap analysis suggests that Drosophila YPEL3 ( dYPEL3 ) is predominantly expressed in subsets of neurons, including nociceptors. Analysis on chemical nociception induced by allyl-isothiocyanate (AITC), a natural chemical stimulant, revealed a reduced nociceptive response in dYPEL3 mutants. Subsequent circuit analysis showed a reduction in the activation of second-order neurons (SONs) in the pathway without affecting nociceptor activation upon AITC treatment. Although the gross axonal and dendritic development of nociceptors was not affected, the synaptic contact between nociceptors and SONs were decreased by dYPEL3 mutations. Together, these suggest that the frameshift mutation in human YPEL3 causes neurological conditions by weakening synaptic connection through presynaptic mechanisms.