Translational and Regulatory Sciences
Online ISSN : 2434-4974
Experimental Animal
Long terminal repeat insertion in Kit causes unilateral renal agenesis in rats
Shiori ARAAyako MIYAZAKIHieu HOANG TRUNGMayuko YOKOEYuki NAKAGAWATakehito KANEKOTakashi KURAMOTO
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2020 Volume 2 Issue 1 Pages 30-35

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Abstract

Human unilateral renal agenesis (URA) is a urinary malformation characterized by congenital absence of one kidney. The inbred rat strain ACI is a known animal model for studying URA. Recently, a single locus responsible for URA, designated renal agenesis 1 (Renag1), has been mapped to a 379-kb interval that contains a single gene, Kit, which encodes c-kit that plays important roles in stem cell survival, migration, and differentiation. Within the Renag1 interval, an insertion of a long terminal repeat (LTR) sequence has been found as a major variation specific for the ACI genome, and the LTR has been strongly suggested to be a causative factor of URA. Here, we removed the LTR from the ACI Kit gene by the CRISPR/Cas9 system and examined whether these gene-modified rats exhibited URA. Three gene-modified ACI strains were developed that lacked the LTR and flanking sequences of different lengths. Out of a total of 125 gene-modified rats observed, none of the rats exhibited URA. Besides URA, abdominal white spotting, Irish, has also been mapped to the Renag1 locus. We also observed that the gene-modified ACI rats did not exhibit Irish spotting. Thus, we concluded that the LTR was causative of both URA and Irish spotting in ACI rats. This study suggests that the Kit signaling pathway plays an important role in kidney development and that ACI rats would be a promising animal model for regenerative medicine therapy of kidney diseases.

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