title: Outside the box signaling: secreted factors modulate GnRH receptor-mediated gonadotropin regulation.
abstract: Control of gene expression following activation of membrane receptors results from the regulation of intracellular signaling pathways and transcription factors. Accordingly, research to elucidate the regulatory control circuits and cellular data processing mechanisms focuses on intracellular mechanisms. While autocrine and paracrine signaling are acknowledged in endocrinology, secreted factors are not typically recognized as fundamental components of the pathways connecting cell surface receptors to gene control in the nucleus. Studies of the gonadotrope suggest that extracellular regulatory loops may play a central role in the regulation of gonadotropin gene expression by gonadotropin-releasing hormone (GnRH) receptor activation. We review emerging evidence for this phenomenon, which we refer to as exosignaling, in gonadotropin gene control and in other receptor-mediated signaling systems. We propose that basic signaling circuit modules controlling gene expression can be seamlessly distributed across intracellular and exosignaling components that together orchestrate the precise physiological control of gene expression.
authors.affiliation: Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: hanna.pincas@mssm.edu.
authors.forename: Hanna
authors.initials: H
authors.lastname: Pincas
authors.affiliation: Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: soon-gang.choi@mssm.edu.
authors.forename: Soon Gang
authors.initials: SG
authors.lastname: Choi
authors.affiliation: Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: qian.wang@mssm.edu.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: jingjing.jia@mssm.edu.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jia
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of California, Davis, CA 95616, United States. Electronic address: jlturgeon@ucdavis.edu.
authors.forename: Judith L
authors.initials: JL
authors.lastname: Turgeon
authors.affiliation: Department of Neurology, Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: stuart.sealfon@mssm.edu.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D052681:Gonadotrophs / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D019899:Paracrine Communication / Q000502:physiology*; D011966:Receptors, LHRH / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011966:Receptors, LHRH
keywords: Autocrine; Exosignaling; GnRH; Inhibin α; PACAP; Prostaglandins