Abstract
Alkaline phosphatase (ALP) is a ubiquitous membrane-bound glycoprotein capable of providing inorganic phosphate by catalyzing the hydrolysis of organic phosphate esters, or removing inorganic pyrophosphate that inhibits calcification. In humans, four forms of ALP cDNA have been cloned, among which tissue-nonspecific ALP (TNSALP) (TNSALP) is widely distributed in the liver, bone, and kidney, making it an important marker in clinical and basic research. Interestingly, TNSALP is highly expressed in juvenile cells, such as pluripotent stem cells (i.e., embryonic stem cells and induced pluripotent stem cells (iPSCs)) and somatic stem cells (i.e., neuronal stem cells and bone marrow mesenchymal stem cells). Hypophosphatasia is a genetic disorder causing defects in bone and tooth development as well as neurogenesis. Mutations in the gene coding for TNSALP are thought to be responsible for the abnormalities, suggesting the essential role of TNSALP in these events. Moreover, a reverse-genetics-based study using mice revealed that TNSALP is important in bone and tooth development as well as neurogenesis. However, little is known about the role of TNSALP in the maintenance and differentiation of juvenile cells. Recently, it was reported that cells enriched with TNSALP are more easily reprogrammed into iPSCs than those with less TNSALP. Furthermore, in bone marrow stem cells, ALP could function as a “signal regulator” deciding the fate of these cells. In this review, we summarize the properties of ALP and the background of ALP gene analysis and its manipulation, with a special focus on the potential role of TNSALP in the generation (and possibly maintenance) of juvenile cells.
Highlights
A mutation in the gene coding for tissue-nonspecific ALP (TNSALP) has been closely associated with a severe skeletal deformity disease termed “hypophosphatasia (HPP),” which is characterized by several pathological abnormalities, including rickets, osteomalacia, epilepsy-like seizures associated with vitamin B6 deficiency, muscle weakness, and respiratory disturbance [14,15]
When the Alpltm1(cre)Nagy mice were crossed with the double-reporter line, Z/AP [49], carrying a floxed sequence containing loxP site, lacZ gene, neor, transcription stopper, loxP site, and a gene encoding human alkaline phosphatase, the resulting bigenic offspring exhibited expression of reporter genes in primordial germ cell (PGC) at E9.5–10.5
AMPK is activated by the increased adenosine monophosphate (AMP), which is generated through the sequential degradation/hydrolysis reactions of polyP catalyzed by TNSALP
Summary
At least four forms of ALP cDNA have been cloned: intestinal ALP (IALP or IAP; restricted to the intestine), placental ALP (PLALP, PLAP or Regan isozyme; restricted to the placenta), germ cell ALP (GCALP, GCAP or NAGAO isozyme; restricted to early embryonic cells), and liver/bone/kidney ALP (L/B/K ALP; widely distributed) [1,16]. The gene for TNSALP is located on chromosome 1, and the genes for the other three isoforms (IALP, PLALP, and GCALP) are located on chromosome 2 [16]. PLALP, GCALP, IALP, and TNSALP belong to the ALP family. Skynner et al [20] demonstrated that systemic overexpression of human PLALP has no adverse effects on mouse development or viability using transgenic (Tg) mouse lines. Based on these findings, they suggested that PLALP could be used as a reporter gene in conjunction with, or as an alternative to ß-galactosidase (ß-gal; encoded by lacZ). Unknown Fat absorption, Detoxification of lipopolysaccharide Skeletal mineralization Fat absorption, detoxification of lipopolysaccharide Early embryogenesis
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