Overexpression of arginase I in enterocytes of transgenic mice elicits a selective arginine deficiency and affects skin, muscle, and lymphoid development.
BACKGROUND
Arginine is required for the detoxification of ammonia and the synthesis of proteins, nitric oxide, agmatine, creatine, and polyamines, and it may promote lymphocyte function. In suckling mammals, arginine is synthesized in the enterocytes of the small intestine, but this capacity is lost after weaning.


OBJECTIVE
We investigated the significance of intestinal arginine production for neonatal development in a murine model of chronic arginine deficiency.


METHODS
Two lines of transgenic mice that express different levels of arginase I in their enterocytes were analyzed.


RESULTS
Both lines suffer from a selective but quantitatively different reduction in circulating arginine concentration. The degree of arginine deficiency correlated with the degree of retardation of hair and muscle growth and with the development of the lymphoid tissue, in particular Peyer's patches. Expression of arginase in all enterocytes was necessary to elicit this phenotype. Phenotypic abnormalities were reversed by daily injections of arginine but not of creatine. The expression level of the very arginine-rich skin protein trichohyalin was not affected in transgenic mice. Finally, nitric oxide synthase-deficient mice did not show any of the features of arginine deficiency.


CONCLUSIONS
Enterocytes are important for maintaining arginine homeostasis in neonatal mice. Graded arginine deficiency causes graded impairment of skin, muscle, and lymphoid development. The effects of arginine deficiency are not mediated by impaired synthesis of creatine or by incomplete charging of arginyl-transfer RNA.
de Jonge
Wouter J
WJ
Department of Anatomy and Embryology, Academic Medical Center, University of Amsterdam, Netherlands.
Hallemeesch
Marcella M
MM
Kwikkers
Karin L
KL
Ruijter
Jan M
JM
de Gier-de Vries
Corrie
C
van Roon
Marian A
MA
Meijer
Alfred J
AJ
Marescau
Bart
B
de Deyn
Peter P
PP
Deutz
Nicolaas E P
NE
Lamers
Wouter H
WH
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001119:Arginase / Q000235:genetics*; D001120:Arginine / Q000008:administration & dosage / Q000032:analysis / Q000172:deficiency*; D020895:Enterocytes / Q000201:enzymology*; D015870:Gene Expression; D006197:Hair / Q000254:growth & development; D007381:Intermediate Filament Proteins; D007413:Intestinal Mucosa / Q000254:growth & development / Q000473:pathology; D008221:Lymphoid Tissue / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000172:deficiency; D010581:Peyer's Patches / Q000254:growth & development / Q000473:pathology; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics; D012867:Skin / Q000254:growth & development* / Q000473:pathology
D007381:Intermediate Filament Proteins; D011498:Protein Precursors; C016159:trichohyalin; D001120:Arginine; D019001:Nitric Oxide Synthase; D001119:Arginase