INVESTIGADORES
HALPERIN Julia
artículos
Título:
Prolactin signaling through the short form of its receptor represses forkhead transcription factor FOXO3 and its target gene galt causing a severe ovarian defect
Autor/es:
HALPERIN J, DEVI SY, ELIZUR S, STOCCO C, SHEHU A, REBOURCET D, UNTERMAN TG, LESLIE ND, LE J, BINART N, GIBORI G.
Revista:
MOLECULAR ENDOCRINOLOGY
Editorial:
ENDOCRINE SOC
Referencias:
Año: 2008 vol. 22 p. 513 - 522
ISSN:
0888-8809
Resumen:
Prolactin (PRL) is a hormone with over 300 biological activities.
Although the signaling pathway downstream of the long form of its
receptor (RL) has been well characterized, little is known about PRL
actions upon activation of the short form (RS). Here, we show that mice
expressing only RS exhibit an ovarian phenotype of accelerated
follicular recruitment followed by massive follicular death leading to
premature ovarian failure. Consequently, RS-expressing ovaries of young
adults are depleted of functional follicles and formed mostly by
interstitium. We also show that activation of RS represses the
expression of the transcription factor Forkhead box O3 (FOXO3) and that
of the enzyme galactose-1-phosphate uridyltransferase (Galt), two
proteins known to be essential for normal follicular development. Our
finding that FOXO3 regulates the expression of Galt and enhances its
transcriptional activity indicates that it is the repression of FOXO3
by PRL acting through RS that prevents Galt expression in the ovary and
causes follicular death. Coexpression of RL with RS prevents PRL
inhibition of Galt, and the ovarian defect is no longer seen in RS
transgenic mice that coexpress RL, suggesting that RL prevents
RS-induced ovarian impairment. In summary, we show that PRL signals
through RS and causes, in the absence of RL, a severe ovarian pathology
by repressing the expression of FOXO3 and that of its target gene Galt.
We also provide evidence of a link between the premature ovarian
failure seen in mice expressing RS and in mice with FOXO3 gene deletion
as well as in human with Galt mutation.