The endothelial cells forming the blood-brain barrier (BBB) are highly specialized to allow precise control over the substances that leave or enter the brain. An elaborate network of complex tight junctions (TJ) between the endothelial cells forms the structural basis of the BBB and restricts the paracellular diffusion of hydrophilic molecules. Additonally, the lack of fenestrae and the extremely low pinocytotic activity of endothelial cells of the BBB inhibit the transcellular passage of molecules across the barrier. On the other hand, in order to meet the high metabolic needs of the tissue of the central nervous system (CNS), specific transport systems selectively expressed in the membranes of brain endothelial cells in capillaries mediate the directed transport of nutrients into the CNS or of toxic metabolites out of the CNS. Whereas the characteristics of the mature BBB endothelium are well described, the cellular and molecular mechanisms that control the development, differentiation and maintenance of the highly specialized endothelial cells of the BBB remain unknown to date, despite the recent explosion in our knowledge of the growth factors and their receptors specifically acting on vascular endothelium during development. This review summarizes our current knowledge of the cellular and molecular mechanisms involved in the development and maintenance of the BBB.

https://www.cell.com/trends/neurosciences/pdf/0166-2236(90)90043-A.pdf

Development of the Blood-Brain Barrier

Biochemistry, localization and functional roles of ecto-nucleotidases in the nervous system

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common form of human myelopathy caused by a compression of the spinal cord by ectopic ossification of spinal ligaments. To elucidate the genetic basis for OPLL, we have been studying the ttw (tiptoe walking; previously designated twy) mouse, a naturally occurring mutant which exhibits ossification of the spinal ligaments very similar to human OPLL (refs 3,4). Using a positional candidate-gene approach, we determined the ttw phenotype is caused by a nonsense mutation (glycine 568 to stop) in the Npps gene which encodes nucleotide pyrophosphatase. This enzyme regulates soft-tissue calcification and bone mineralization by producing inorganic pyrophosphate, a major inhibitor of calcification. The accelerated bone formation characteristic of ttw mice is likely to result from dysfunction of NPPS caused by predicted truncation of the gene product, resulting in the loss of more than one-third of the native protein. Our results may lead to novel insights into the mechanism of ectopic ossification and the aetiology of human OPLL.

Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine

Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family

Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1.

Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene.

PC-1 is an alloantigen of murine plasma cells. Its close association with secretory function in lymphoid cells previously raised the question of whether PC-1 was part of the secretory apparatus. In addition to its expression on lymphocytes, PC-1 had been known to be present in liver, brain, and kidney, although the data were derived almost entirely from bulk absorption studies of polyclonal alloantisera, and virtually nothing was known about the nature of the cells expressing PC-1 in these organs. If PC-1 was functionally involved in the secretory process. it might be expected to be present at secretory sites within these and other organs. We now report the results of an immunohistochemical survey of the distribution of PC-1 in a variety of non-lymphoid organs, using a mAb. The PC-1 Ag was found in a small number of highly discrete locations that were mostly, but not exclusively, associated with epithelia. Sites of strong expression included the distal convoluted tubule of the kidney, ducts of the salivary glands, epididymis, proximal part of the vas deferens, and chondrocytes. The PC-1 glycoprotein was also found in the capillaries of the brain, but did not appear to be present in capillaries elsewhere, a pattern that is strikingly similar to that of the receptor for the iron transport protein, transferrin. Negative sites included the thyroid, pancreas, choroid plexus, smooth and striated muscle, stomach, small and large intestine, gall bladder, renal glomeruli, testis, and seminal vesicles. These results are not consistent with a generalized role for PC-1 in secretion, but are compatible with a role in a specialized subset of macromolecular transport events.

A R Harahap

Papers

Distribution of the murine plasma cell antigen PC-1 in non-lymphoid tissues.