Mice lacking the sodium-dependent phosphate import protein, PiT1 (SLC20A1), have a severe defect in terminal erythroid differentiation and early B cell development

Abstract

Phosphate is critical in multiple biological processes (phosphorylation reactions, ATP production, and DNA structure and synthesis). It remains unclear how individual cells initially sense changes in phosphate availability and the cellular consequences of these changes. PiT1 (or SLC20A1) is a constitutively expressed, high-affinity sodium-dependent phosphate import protein. In vitro data suggest that PiT1 serves a direct role in mediating cellular proliferation; its role in vivo is unclear. We have discovered that mice lacking PiT1 develop a profound underproduction anemia characterized by mild macrocytosis, dyserythropoiesis, increased apoptosis, and a near complete block in terminal erythroid differentiation. In addition, the animals are severely B cell lymphopenic because of a defect in pro–B cell development and mildly neutropenic. The phenotype is intrinsic to the hematopoietic system, is associated with a defect in cell cycle progression, and occurs in the absence of changes in serum phosphate or calcium concentrations and independently of a change in cellular phosphate uptake. The severity of the anemia and block in terminal erythroid differentiation and B cell lympho-penia are striking and suggest that PiT1 serves a fundamental and nonredundant role in murine terminal erythroid differentiation and B cell development. Intriguingly, as the anemia mimics the ineffective erythropoiesis in some low-grade human myelodysplastic syndromes, this murine model might also provide pathologic insight into these disorders.

Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction

“…Recently, functions of PiT1 that are independent of its role in phosphate transport have been identified. PiT1 is involved in regulation of proliferation, density, and adhesion (Beck et al, 2009;Byskov et al, 2012;Kongsfelt et al, 2014), embryonic mouse liver development (Beck et al, 2010), tumor necrosis factor (TNF)-induced apoptosis (Sala€ un et al, 2010), and erythroid and B cell differentiation (Forand et al, 2013;Liu et al, 2013). How PiT1 drives these different functions is currently unknown.…”

Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells

“…Also, Salaun et al showed that a Pi uptake-deficient PiT-1 mutant reduced the rate of apoptosis in HeLa cells treated with Tumor Necrosis Factor-α [23]. Finally, PiT-1 regulation of hematopoietic stem cell differentiation was found to be Pi uptake-independent [27, 28]. However, none of those studies identified the cell signaling pathway required for transport-independent PiT-1 functions.…”

Renal phosphate transporters

“…Pit-1 and Pit-2 may have redundant roles in vascular calcification [21] and bone mineralization [22], according to two recent reports showing enhanced Pit-2 expression under conditions in which Pit-1 expression is compromised. However, the functions of the two proteins do not entirely overlap as evidenced by studies showing severe defects in erythroid differentiation in Pit-1-deficient animals [23].…”