Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice.
FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb-null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.
Departments of Molecular and Integrative Physiology and Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160.
Huizhen
H
Wang
Melissa
M
Larson
Albina
A
Jablonka-Shariff
Christopher A
CA
Pearl
William L
WL
Miller
P Michael
PM
Conn
Irving
I
Boime
T Rajendra
TR
Kumar
D000704:Analysis of Variance; D000818:Animals; D005075:Biological Evolution; D015153:Blotting, Western; D005260:Female; D005298:Fertility / Q000502:physiology; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D052681:Gonadotrophs / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D006080:Ovarian Follicle / Q000378:metabolism; D010053:Ovary / Q000378:metabolism / Q000502:physiology*; D010060:Ovulation / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
dense core granules; folliculogenesis; protein sorting; regulated secretion