Deficiency of liver arginase (AI) causes hyperargininemia (OMIM 207800), a disorder characterized by progressive mental impairment, growth retardation, and spasticity and punctuated by sometimes fatal episodes of hyperammonemia. We constructed a knockout mouse strain carrying a nonfunctional AI gene by homologous recombination. Arginase AI knockout mice completely lacked liver arginase (AI) activity, exhibited severe symptoms of hyperammonemia, and died between postnatal days 10 and 14. During hyperammonemic crisis, plasma ammonia levels of these mice increased >10-fold compared to those for normal animals. Livers of AI-deficient animals showed hepatocyte abnormalities, including cell swelling and inclusions. Plasma amino acid analysis showed the mean arginine level in knockouts to be approximately fourfold greater than that for the wild type and threefold greater than that for heterozygotes; the mean proline level was approximately one-third and the ornithine level was one-half of the proline and ornithine levels, respectively, for wild-type or heterozygote mice-understandable biochemical consequences of arginase deficiency. Glutamic acid, citrulline, and histidine levels were about 1.5-fold higher than those seen in the phenotypically normal animals. Concentrations of the branched-chain amino acids valine, isoleucine, and leucine were 0.4 to 0.5 times the concentrations seen in phenotypically normal animals. In summary, the AI-deficient mouse duplicates several pathobiological aspects of the human condition and should prove to be a useful model for further study of the disease mechanism(s) and to explore treatment options, such as pharmaceutical administration of sodium phenylbutyrate and/or ornithine and development of gene therapy protocols.Arginase (EC 3.5.3.1) is the fifth and final enzyme of the urea cycle, the major pathway for the detoxification of ammonia in mammals. There are at least two forms of arginase in mammals, AI and AII, located in the cytoplasm and mitochondrion, respectively. The principal ureagenic enzyme activity (AI) is most abundant in normal mammalian liver and acts in coordination with the other enzymes of the urea cycle to sequester and eliminate excess nitrogen from the body (7). The second form (AII) is found in many organs, with the highest levels found in kidney and prostate and lower levels in macrophages, lactating mammary glands, and brain, often in the absence of the other urea cycle enzymes (7,18). In humans, deficiency of the liver isoform (AI) causes hyperargininemia (OMIM 207800; Online Mendelian Inheritance in Man [http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbϭOMIM]), a metabolic disorder characterized by neurological impairment, with deterioration of the cortex and pyramidal tracts and progressive dementia, spasticity, and growth retardation and punctuated by infrequently fatal episodes of hyperammonemia (7

Arginase I (AI), the fifth and final enzyme of the urea cycle, detoxifies ammonia as part of the urea cycle. In previous studies from others, AI was not found in extrahepatic tissues except in primate blood cells, and its roles outside the urea cycle have not been well recognized. In this study we undertook an extensive analysis of arginase expression in postnatal mouse tissues by in situ hybridization (ISH) and RT-PCR. We also compared arginase expression patterns with those of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT). We found that, outside of liver, AI was expressed in many tissues and cells such as the salivary gland, esophagus, stomach, pancreas, thymus, leukocytes, skin, preputial gland, uterus and sympathetic ganglia. The expression was much wider than that of arginase II, which was highly expressed only in the intestine and kidney. Several co-localization patterns of AI, ODC, and OAT have been found: (a) AI was co-localized with ODC alone in some tissues; (b) AI was co-localized with both OAT and ODC in a few tissues; (c) AI was not co-localized with OAT alone in any of the tissues examined; and (d) AI was not co-localized with either ODC or OAT in some tissues. In contrast, AII was not co-localized with either ODC or OAT alone in any of the tissues studied, and co-localization of AII with ODC and OAT was found only in the small intestine. The co-localization patterns of arginase, ODC, and OAT suggested that AI plays different roles in different tissues. The main roles of AI are regulation of arginine concentration by degrading arginine and production of ornithine for polyamine biosynthesis, but AI may not be the principal enzyme for regulating glutamate biosynthesis in tissues and cells.

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The studies on the exact lineage composition of NG2 expressing progenitors in the forebrain have been controversial. A number of studies have revealed the heterogeneous nature of postnatal NG2 cells. However, NG2 cells found in embryonic dates are far less understood. Our study indicates that early NG2 progenitors from a ventral origin (i.e., before embryonic day 16.5) tangentially migrate out of the medial ganglionic eminence and give rise to interneurons in deep layers of the dorsal cerebral cortex. The majority of myelinating oligodendrocytes found in both cortical gray and white matters are, in contrast, derived from NG2 progenitors with a neonatal subventricular zone origin. Our lineage tracing data reflect the heterogeneous nature of NG2 progenitor populations and define the relationship between lineage divergence and spatiotemporal origins. Beyond the typical lineage tracing studies of NG2 + cells, by costaining with lineage-specific markers, our study addresses the origins of heterogeneity and its implications in the differentiation potentials of NG2 + progenitors.lineage differentiation T he relationship between progenitor origins and their possible terminal cell fates in the central nervous system (CNS) development is a complex question that remains to be fully addressed. Depending on the origin from which a progenitor cell arises, physical and molecular regulatory mechanisms define both cell identity and direct specific lineage potentials during differentiation and migration. For example, cortical pyramidal neurons are generated in the ventricular zone (VZ) of the pallium and are guided by radial glia to their final position in the cortical plate (1, 2). However, cortical interneurons born in subpallium germinal zones during early embryonic dates tangentially migrate to the cortical plate up to the neonatal period. Not only neurons but also the differentiation of glial cells follow a specific spatial and temporal patterning (3, 4). The developmental origin of oligodendrocytes (OLs) is a longstanding controversial issue with many valid hypotheses (5). One hypothesis suggests that OLs are developed throughout all regions of the CNS, with multiple and diverse developmental origins that provide the progenitor sources of all OLs (6, 7). This hypothesis was challenged in the early 1990s as a series of observations suggested that commitment to the OL lineage occurs in a specialized domain of the ventral VZ in development of the spinal cord and forebrain (8). Both strategies provide mature OLs for myelination, but separate and distinct developmental regulatory strategies that direct the OL development are required for each scenario.The subpallium germinal zones are divided into three areas: the medial ganglionic eminence (MGE), the lateral ganglionic eminence, and the caudal ganglionic eminence. The distribution of cortical interneurons correlates with the origin of their progenitors (9, 10). Additional genetic studies have demonstrated that NG2 cells in the subpallium give rise to cortical interneurons (11)....