ATXN10 Is Required for Embryonic Heart Development and Maintenance of Epithelial Cell Phenotypes in the Adult Kidney and Pancreas.

Melissa R Bentley-Ford,Jeremy F Reiter,Courtney J Haycraft,Bradley K Yoder,Jeremy B Foote,Mandy J Croyle,Kelsey R Clearman,Reagan S Andersen

doi:10.3389/fcell.2021.705182

Abstract

Atxn10 is a gene known for its role in cytokinesis and is associated with spinocerebellar ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes nephronophthisis (NPHP) and Joubert syndrome (JBTS), which are caused by the disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here, we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue-specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt ATXN10 systemically at postnatal stages, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial-to-mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively, this study identifies ATXN10 as an essential protein for survival.

Highlights

Ataxin10 (Atxn10) is most commonly associated with spinocerebellar ataxia type 10 (SCA10), which is caused by an ATTCT pentanucleotide expansion within intron 9 (Matsuura et al, 2000)
Overexpression of ATXN10-EGFP in inner medullary collecting duct (IMCD) cells supports a predominantly cytoplasmic expression pattern; enrichment of ATXN10-EGFP near FGFR1OP (FOP)-positive centrioles or basal bodies is seen in 79.3% of the transfected cells, regardless of whether they had a primary cilium
In mouse embryonic fibroblasts (MEFs) generated from Atxn10KO embryos, there was a trend toward fewer cilia, but these differences were not statistically significant between Atxn10KO (33.5%) and control (59.8%) cells (p 0.07) (Figure 1B)

Summary

Introduction

Ataxin (Atxn10) is most commonly associated with spinocerebellar ataxia type 10 (SCA10), which is caused by an ATTCT pentanucleotide expansion within intron 9 (Matsuura et al, 2000). The only reported human incidence of Atxn mutation (IVS8-3T > G) in the protein-coding region was observed in three Turkish siblings from a consanguineous family. This mutation resulted in Nephronophthisis-like kidney defects that led to death as infants (Sang et al, 2011). NPHP is a form of medullary cystic kidney disease with associated nephron loss (Luo and Tao, 2018), while JBTS is autosomal recessive or X-linked cerebellar ataxia associated with cerebellar hypoplasia (Romani et al, 2013) Both NPHP and JBTS fall into the class of disorders collectively termed ciliopathies. These small microtubule-based appendages are present on the surface of nearly every mammalian cell type and are crucial for mediating many cell signaling events (Sharma et al, 2008)

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