Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway.
The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3alpha, the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (Nt(N)-amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1(-/-) mouse strains lacked the Nt(N)-amidase activity but retained glutamine-specific Nt(Q)-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1(-/-) fibroblasts. The Ntan1(-/-) mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains.
Kwon
Y T
YT
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Balogh
S A
SA
Davydov
I V
IV
Kashina
A S
AS
Yoon
J K
JK
Xie
Y
Y
Gaur
A
A
Hyde
L
L
Denenberg
V H
VH
Varshavsky
A
A
D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001216:Asparagine; D001522:Behavior, Animal; D004924:Escape Reaction; D005260:Female; D015870:Gene Expression; D007424:Intracellular Fluid / Q000378:metabolism; D007858:Learning; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D011597:Psychomotor Performance; D012919:Social Behavior
D001216:Asparagine; D000581:Amidohydrolases; C425491:N-terminal asparagine amidohydrolase