Negative feedback governs gonadotrope frequency-decoding of gonadotropin releasing hormone pulse-frequency.
The synthesis of the gonadotropin subunits is directed by pulsatile gonadotropin-releasing hormone (GnRH) from the hypothalamus, with the frequency of GnRH pulses governing the differential expression of the common alpha-subunit, luteinizing hormone beta-subunit (LHbeta) and follicle-stimulating hormone beta-subunit (FSHbeta). Three mitogen-activated protein kinases, (MAPKs), ERK1/2, JNK and p38, contribute uniquely and combinatorially to the expression of each of these subunit genes. In this study, using both experimental and computational methods, we found that dual specificity phosphatase regulation of the activity of the three MAPKs through negative feedback is required, and forms the basis for decoding the frequency of pulsatile GnRH. A fourth MAPK, ERK5, was shown also to be activated by GnRH. ERK5 was found to stimulate FSHbeta promoter activity and to increase FSHbeta mRNA levels, as well as enhancing its preference for low GnRH pulse frequencies. The latter is achieved through boosting the ultrasensitive behavior of FSHbeta gene expression by increasing the number of MAPK dependencies, and through modulating the feedforward effects of JNK activation on the GnRH receptor (GnRH-R). Our findings contribute to understanding the role of changing GnRH pulse-frequency in controlling transcription of the pituitary gonadotropins, which comprises a crucial aspect in regulating reproduction. Pulsatile stimuli and oscillating signals are integral to many biological processes, and elucidation of the mechanisms through which the pulsatility is decoded explains how the same stimulant can lead to various outcomes in a single cell.
Lim
Stefan
S
National University of Singapore, Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences, Singapore, Republic of Singapore.
Pnueli
Lilach
L
Tan
Jing Hui
JH
Naor
Zvi
Z
Rajagopal
Gunaretnam
G
Melamed
Philippa
P
D000465:Algorithms; D000818:Animals; D025461:Feedback, Physiological; D037201:Follicle Stimulating Hormone, beta Subunit / Q000378:metabolism; D005786:Gene Expression Regulation; D052681:Gonadotrophs / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D008954:Models, Biological; D015233:Models, Statistical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012984:Software
D037201:Follicle Stimulating Hormone, beta Subunit; D007987:Gonadotropin-Releasing Hormone; D048054:Mitogen-Activated Protein Kinase 7; D048670:MAP Kinase Kinase 4