Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality

Abstract

Absorption of dietary phosphate (Pi) across intestinal epithelia is a regulated process mediated by transcellular and paracellular pathways. Although hyperphosphatemia is a risk factor for the development of cardiovascular disease, the amount of ingested Pi in a typical Western diet is above physiological needs. While blocking intestinal absorption has been suggested as a therapeutic approach to prevent hyperphosphatemia, a complete picture regarding the identity and regulation of the mechanism(s) responsible for intestinal absorption of Pi is missing. The Na+/Pi cotransporter NaPi-IIb is a secondary active transporter encoded by the Slc34a2 gene. This transporter has a wide tissue distribution and within the intestinal tract is located at the apical membrane of epithelial cells. Based on mouse models deficient in NaPi-IIb, this cotransporter is assumed to mediate the bulk of active intestinal absorption of Pi. However, whether or not this is also applicable to humans is unknown, since human patients with inactivating mutations in SLC34A2 have not been reported to suffer from Pi depletion. Thus, mice may not be the most appropriate experimental model for the translation of intestinal Pi handling to humans. Here, we describe the generation of a rat model with Crispr/Cas-driven constitutive depletion of Slc34a2. Slc34a2 heterozygous rats were indistinguishable from wild type animals under standard dietary conditions as well as upon 3 days feeding on low Pi. However, unlike in humans, homozygosity resulted in perinatal lethality.

SRRM2 splicing factor modulates cell fate in early development

“…BNC2 and PCYT2 are important for the differentiation and maturation of mesenchyme and muscle, respectively, both with origin in the mesodermal germ layer ( Vanhoutteghem et al, 2009 ; Zhu et al, 2009 ). Pcyt2 and Slc39a4 are essential genes for mouse development, as complete knockout mice die during embryogenesis ( Fullerton et al, 2007 ; Pastor-Arroyo et al, 2021 ). Our results reveal that the transcriptional profile of Srrm2 +/− cells is consistent with an altered pluripotent state that affects several development-related genes and is compatible with a mixture of different cellular states within the Srrm2 +/− cell cultures.…”

SLC34A2 Targets in Calcium/Phosphorus Homeostasis of Mammary Gland and Involvement in Development of Clinical Mastitis in Dairy Cows

“…Previous studies have shown that SLC34A2 is widely expressed in multiple organs and plays a critical role in several malignant tumors [14,15]. Depletion of SLC34A2/NaPi-IIb causes perinatal mortality in rats [11]. This finding suggests that SLC34A2 is closely associated with perinatal diseases.…”

“…Enhanced availability and absorption of P cause P overload and negatively affect Ca metabolism [10]. Solute carrier (SLC) transporters, the largest family of transmembrane proteins, facilitate the exchange of various substances, including endogenous and xenobiotic compounds, using an electrochemical or ion gradient [11]. Type II Na/Pi co-transporter (NaPi2b), a multitransmembrane sodium-dependent phosphate transporter, is encoded by solute carrier family 34 member 2 (SLC34A2), which is responsible for transcellular inorganic phosphate absorption [12,13].…”

SRRM2 splicing factor modulates cell fate in early development

“…BNC2 and PCYT2 are important for the differentiation and maturation of mesenchyme and muscle, respectively, both with origin in the mesodermal germ layer (Vanhoutteghem et al, 2009;Zhu et al, 2009). Pcyt2 and Slc39a4 are essential genes for mouse development, as complete knockout mice die during embryogenesis (Fullerton et al, 2007;Pastor-Arroyo et al, 2021). Our results reveal that the transcriptional profile of Srrm2 +/cells is consistent with an altered pluripotent state that affects several development-related genes and is compatible with a mixture of different cellular states within the Srrm2 +/cell cultures.…”