Defective propagation of signals generated by sympathetic nerve stimulation in the liver of connexin32-deficient mice.
The gap junctional protein connexin32 is expressed in hepatocytes, exocrine pancreatic cells, Schwann cells, and other cell types. We have inactivated the connexin32 gene by homologous recombination in the mouse genome and have generated homozygous connexin32-deficient mice that were viable and fertile but weighed on the average approximately 17% less than wild-type controls. Electrical stimulation of sympathetic nerves in connexin32-deficient liver triggered a 78% lower amount of glucose mobilization from glycogen stores, when compared with wild-type liver. Thus, connexin32-containing gap junctions are essential in mouse liver for maximal intercellular propagation of the noradrenaline signal from the periportal (upstream) area, where it is received from sympathetic nerve endings, to perivenous (downstream) hepatocytes. In connexin32-defective liver, the amount of connexin26 protein expressed was found to be lower than in wild-type liver, and the total area of gap junction plaques was approximately 1000-fold smaller than in wild-type liver. In contrast to patients with connexin32 defects suffering from X chromosome-linked Charcot-Marie-Tooth disease (CMTX) due to demyelination in Schwann cells of peripheral nerves, connexin32-deficient mice did not show neurological abnormalities when analyzed at 3 months of age. It is possible, however, that they may develop neurodegenerative symptoms at older age.
Nelles
E
E
Abteilüng Molekulargenetik, Universität Bonn, Germany.
Bützler
C
C
Jung
D
D
Temme
A
A
Gabriel
H D
HD
Dahl
U
U
Traub
O
O
Stümpel
F
F
Jungermann
K
K
Zielasek
J
J
Toyka
K V
KV
Dermietzel
R
R
Willecke
K
K
D000818:Animals; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000503:physiopathology; D000072259:Connexin 26; D017630:Connexins / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D004558:Electric Stimulation; D005260:Female; D005614:Freeze Fracturing; D017629:Gap Junctions / Q000378:metabolism; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D008099:Liver / Q000294:innervation* / Q000648:ultrastructure; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009638:Norepinephrine / Q000494:pharmacology; D010641:Phenotype; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D000097002:Gap Junction beta-1 Protein
D000072259:Connexin 26; D017630:Connexins; D005947:Glucose; D008112:Liver Glycogen; D009638:Norepinephrine; D000097002:Gap Junction beta-1 Protein