Age-related development of a heterozygous phenotype in solitary neurons of the homozygous Brattleboro rat.
A single-base deletion in the single-copy vasopressin gene is the cause of diabetes insipidus in the homozygous Brattleboro rat (di/di). It results in the synthesis of an altered vasopressin precursor of which the axonal transport is blocked. Paradoxically, a small number of solitary hypothalamic neurons displays all the immunoreactivities of the wild-type vasopressin precursor (i.e., vasopressin, neurophysin, and a glycopeptide). In the present paper we provide evidence that these neurons have undergone a switch to a genuine heterozygous (di/+) phenotype; i.e., they contain the immunoreactivities of both the wild-type and the mutated vasopressin precursors. In the neural lobe, glycopeptide fibers are also present, showing that axonal transport of the wild-type precursor is restored. Moreover, the number of neurons displaying this di/+ phenotype increases markedly and in a linear way (from 0.1% up to 3% of the vasopressin cells) with age. These findings indicate that after mitotic division has ceased, genomic alterations occur in somatic neurons in vivo. The molecular event generating the di/+ phenotype in the di/di animal could involve a somatic intrachromosomal gene conversion between the homologous exons of the vasopressin and the related oxytocin genes.
Netherlands Institute for Brain Research, Amsterdam.
F
F
van Leeuwen
E
E
van der Beek
M
M
Seger
P
P
Burbach
R
R
Ivell
D000375:Aging; D000818:Animals; D005260:Female; D005796:Genes; D006020:Glycopeptides / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D007031:Hypothalamus / Q000254:growth & development*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009479:Neuropeptides / Q000032:analysis / Q000235:genetics*; D009481:Neurophysins / Q000235:genetics; D010121:Oxytocin / Q000235:genetics; D010641:Phenotype; D051381:Rats; D011910:Rats, Brattleboro / Q000235:genetics*; D011922:Rats, Mutant Strains / Q000235:genetics*; D014667:Vasopressins / Q000235:genetics
D006020:Glycopeptides; D009479:Neuropeptides; D009481:Neurophysins; D014667:Vasopressins; D010121:Oxytocin