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Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved February 28, 2014 (received for review November 14, 2013)
Significance
Although the two pituitary gonadotropins luteinizing hormone (LH) and FSH are synthesized in the same cell, gonadotrope, their intracellular trafficking and secretion pattern are distinct. LH is released as pulses via the regulated pathway, whereas FSH is constitutively secreted. Why this hormone-specific pattern has evolved and whether the target organ, the ovary, senses specific hormone release pattern is not understood. In this paper, a gonadotrope-specific sorting determinant on LH has been identified, and FSH was diverted into the LH secretory pathway in vivo. FSH released like LH from pituitary dramatically enhanced the ovarian responses. Our studies provide a molecular basis for the evolution of distinct patterns of gonadotropin secretion and explain the origin of estrus cycles in mammals.
Abstract
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.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: tkumar{at}kumc.edu.
Author contributions: T.R.K. designed research; H.W., M.L., and T.R.K. performed research; A.J.-S., C.A.P., W.L.M., P.M.C., and I.B. contributed new reagents/analytic tools; H.W. and T.R.K. analyzed data; and T.R.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1321404111/-/DCSupplemental.
FSH rerouting and ovarian function
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