Interspecies diversity of chloride channel regulators, calcium-activated 3 genes

Abstract

Members of the chloride channel regulators, calcium-activated (CLCA) family, have been implicated in diverse biomedical conditions, including chronic inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, the activation of macrophages, and the growth and metastatic spread of tumor cells. Several observations, however, could not be repeated across species boundaries and increasing evidence suggests that select CLCA genes are particularly prone to dynamic species-specific evolvements. Here, we systematically characterized structural and expressional differences of the CLCA3 gene across mammalian species, revealing a spectrum of gene duplications, e.g., in mice and cows, and of gene silencing via diverse chromosomal modifications in pigs and many primates, including humans. In contrast, expression of a canonical CLCA3 protein from a single functional gene seems to be evolutionarily retained in carnivores, rabbits, guinea pigs, and horses. As an accepted asthma model, we chose the cat to establish the tissue and cellular expression pattern of the CLCA3 protein which was primarily found in mucin-producing cells of the respiratory tract and in stratified epithelia of the esophagus. Our results suggest that, among developmental differences in other CLCA genes, the CLCA3 gene possesses a particularly high dynamic evolutionary diversity with pivotal consequences for humans and other primates that seem to lack a CLCA3 protein. Our data also help to explain previous contradictory results on CLCA3 obtained from different species and warrant caution in extrapolating data from animal models in conditions where CLCA3 may be involved.

The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer

“…Members of the chloride channel regulators, calcium activated (CLCA) family, of proteins have been suggested to possess diverse roles in control of cellular proliferation, differentiation of epithelial cells, transmembrane trafficking of anions, tumour suppression, and the activation of macrophages [ 43 , 44 , 45 , 46 ]. Murine family members mClca1 , mClca2 , and mClca5 (homologous to human CLCA2 ; hCLCA2 ) are expressed in the mammary gland [ 43 , 44 , 47 ].…”

Calcium-activated chloride channel regulator 1 (CLCA1) forms non-covalent oligomers in colonic mucus and has mucin 2–processing properties

“…Murine Clca1 has previously been named Gob-5 and mClca3 but was recently renamed according to the human CLCA nomenclature (6). CLCA1 belongs to a family of CLCAs with four human (hCLCA1–4) and eight murine homologs (mClca1, -2, -3a, -3b, -3c, -4a, -4b, and -4c) of which only CLCA1/Clca1 is secreted (6). The CLCAs share common features and highly conserved protein domains (Fig.…”

Soluble mucus component CLCA1 modulates expression of leukotactic cytokines and BPIFA1 in murine alveolar macrophages but not in bone marrow-derived macrophages

“…The discovery of a signaling link between CLCA1 and BPIFA1 also sheds new light on the alleged role of CLCA1 in anion conductance and liquid homeostasis, which originally gave rise to the designation of this gene family as “chloride channel regulators, calcium-activated” (Patel et al 2009 ). Very recently, conspicuous parallels concerning interspecies diversities and similar microenvironment expression patterns were found between CLCA1 and BPIFA1 (Mundhenk et al 2018 ) which underlines potential overlapping effects of CLCA1 and BPIFA1. In light of several previous and partially contradictory reports on human and mouse CLCA1 and other CLCA proteins modulating anion conductance in epithelial cells (Gruber et al 1998 ; Mundhenk et al 2012 ), it is tempting to speculate that this effect may also involve BPIFA1, which has been well established as a modifier of airway liquid homeostasis, including modulation of the epithelial sodium channel (ENaC) (Gaillard et al 2010 ; Garland et al 2013 ; Hobbs et al 2013 ).…”

“…Substantial genomic, structural, functional, and expressional differences have been described for several orthologous CLCA family members from different species. For example, Clca3 possesses one functional gene copy in several mammalian species but two distinct functional copies in cattle, whereas in humans and in pigs it is a non-functional pseudogene (Gruber and Pauli 1999 ; Mundhenk et al 2018 ; Plog et al 2009 ). Interestingly, in the mouse, two gene duplication events resulted in three apparently functional CLCA3 proteins which are expressed in different cellular niches (Mundhenk et al 2018 ; Patel et al 2009 ).…”

“…For example, Clca3 possesses one functional gene copy in several mammalian species but two distinct functional copies in cattle, whereas in humans and in pigs it is a non-functional pseudogene (Gruber and Pauli 1999 ; Mundhenk et al 2018 ; Plog et al 2009 ). Interestingly, in the mouse, two gene duplication events resulted in three apparently functional CLCA3 proteins which are expressed in different cellular niches (Mundhenk et al 2018 ; Patel et al 2009 ). The Clca4 gene is duplicated in the pig and the mouse with two or three, respectively, apparently distinctly regulated proteins, expressed in different cell types and functional niches (Patel et al 2009 ; Plog et al 2015 ).…”