The 29 amino acid neuropeptide galanin is widely distributed
in the nervous and endocrine systems; highest levels of galanin
synthesis and storage occur within the hypothalamus in the median
eminence, but it is also abundantly expressed in the basal forebrain,
the peripheral nervous system, and gut. To further define the
role played by galanin in the peripheral nervous and endocrine
systems, a mouse strain carrying a loss-of-function germ-line
mutation of the galanin locus, engineered by targeted mutagenesis
in embryonic stem cells, has been generated. The mutation removes
the first five exons containing the entire coding region for
the galanin peptide. Germ-line transmission of the disrupted
galanin locus has been obtained, and the mutation has been bred
to homozygosity on the inbred 12901aHsd background. Phenotypic
analysis of mice lacking a functional galanin gene demonstrate
that these animals are viable, grow normally, and can reproduce.
A marked reduction in both the anterior pituitary prolactin
content and in circulating plasma levels of the hormone is evident.
Lactation is abolished along with abrogation of the proliferative
response of the lactotroph to estrogen. The responses of sensory
neurons to injury in the mutants are markedly impaired. Peripheral
nerve regeneration is reduced with associated long-term functional
deficits. There is a striking reduction in the development of
chronic neuropathic pain. These two phenotypic changes may be
explained, in part, by the observation that a subset of dorsal
root ganglion neurons is lost in the mutant animals, implying
a role for galanin as a trophic cell survival factor. These
initial findings have important implications for our understanding
and potential therapeutic treatment of (a) sensory nerve regeneration
and neuropathic pain and (b) disordered pituitary proliferation
and the development of prolactinoma.
