ABSTRACT
There is increasing evidence for communication among pituitary cells. Hormone-producing pituitary cells may communicate with each other and with folliculostellate cells. The latter cells surround pituitary hormone-producing cells and are connected by tight junctions to form a network that allows for their coordinated function. Folliculostellate cells are targets of cytokines, peptides, and steroid hormones, and produce growth factors and cytokines, including follistatin, the dynamic regulator of follicle-stimulating hormone (FSH) production that binds activin, and limits activin signaling. Pituitary adenylate cyclase-activating peptide (PACAP) and its receptor are found in folliculostellate cells in which they stimulate transcription of the follistatin gene through cyclic adenosine monophosphate/protein kinase A (PKA) signaling. When PACAP increases, follistatin levels increase, and FSH-β mRNA is reduced. PACAP also activates gonadotrophs to stimulate transcription of the gonadotropin α-subunit gene and lengthen the LH-β mRNA, presumably to prolong it half-life, and increases responsiveness to GnRH. Accordingly, PACAP differentially regulates FSH and LH, and may prove to be a key player in reproduction through a novel paracrine mechanism.
KEYWORDS
Pituitary - follicle-stimulating hormone (FSH) - pituitary adenylate cyclase-activating peptide (PACAP) - follistatin - folliculostellate cells
REFERENCES
-
1
Mason A J, Hayflick J S, Zoeller R T et al..
A deletion truncating the gonadotropin-releasing hormone gene is responsible for hypogonadism in the hpg mouse.
Science.
1986;
234
1366-1371
-
2
Tsai P S, Gill J C.
Mechanisms of disease: insights into X-linked and autosomal-dominant Kallmann syndrome.
Nat Clin Pract Endocrinol Metab.
2006;
2
160-171
-
3
Beranova M, Oliveira L M, Bedecarrats G Y et al..
Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.
J Clin Endocrinol Metab.
2001;
86
1580-1588
-
4
Yuen T, Wurmbach E, Ebersole B J, Ruf F, Pfeffer R L, Sealfon S C.
Coupling of GnRH concentration and the GnRH receptor-activated gene program.
Mol Endocrinol.
2002;
16
1145-1153
-
5
Billiard J.
Functional heterogeneity of pituitary gonadotropes in response to a variety of neuromodulators.
Mol Cell Endocrinol.
1996;
123
163-170
-
6
Stojilkovic S S, Iida T, Cesnjaj M, Catt K J.
Differential actions of endothelin and gonadotropin-releasing hormone in pituitary gonadotrophs.
Endocrinology.
1992;
131
2821-2828
-
7
Tsujii T, Ishizaka K, Winters S J.
Effects of pituitary adenylate cyclase-activating polypeptide on gonadotropin secretion and subunit messenger ribonucleic acids in perifused rat pituitary cells.
Endocrinology.
1994;
135
826-833
-
8
Miyata A, Arimura A, Dahl R R et al..
Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.
Biochem Biophys Res Commun.
1989;
164
567-574
-
9
Canny B J, Rawlings S R, Leong D A.
Pituitary adenylate cyclase-activating polypeptide specifically increases cytosolic calcium ion concentration in rat gonadotropes and somatotropes.
Endocrinology.
1992;
130
211-215
-
10
Tsujii T, Winters S J.
Effects of pulsatile pituitary adenylate cyclase activating polypeptide (PACAP) on gonadotropin secretion and subunit mRNA levels in perifused rat pituitary cells.
Life Sci.
1995;
56
1103-1111
-
11
Leupen S M, Levine J E.
Role of protein kinase C in facilitation of luteinizing hormone (LH)-releasing hormone-induced LH surges by neuropeptide Y.
Endocrinology.
1999;
140
3682-3687
-
12
Parker S L, Kalra S P, Crowley W R.
Neuropeptide Y modulates the binding of a gonadotropin-releasing hormone (GnRH) analog to anterior pituitary GnRH receptor sites.
Endocrinology.
1991;
128
2309-2316
-
13
Pincas H, Laverriere J N, Counis R.
Pituitary adenylate cyclase-activating polypeptide and cyclic adenosine 3′,5′-monophosphate stimulate the promoter activity of the rat gonadotropin-releasing hormone receptor gene via a bipartite response element in gonadotrope-derived cells.
J Biol Chem.
2001;
276
23562-23571
-
14
Morel G, Chabot J G, Dubois P M.
Ultrastructural evidence for oxytocin in the rat anterior pituitary gland.
Acta Endocrinol (Copenh).
1988;
117
307-314
-
15
Fauquier T, Lacampagne A, Travo P, Bauer K, Mollard P.
Hidden face of the anterior pituitary.
Trends Endocrinol Metab.
2002;
13
304-309
-
16
Nakajima T, Yamaguchi H, Takahashi K.
S100 protein in folliculostellate cells of the rat pituitary anterior lobe.
Brain Res.
1980;
191
523-531
-
17
Allaerts W, Jeucken P H, Debets R, Hoefakker S, Claassen E, Drexhage H A.
Heterogeneity of pituitary folliculo-stellate cells: implications for interleukin-6 production and accessory function in vitro.
J Neuroendocrinol.
1997;
9
43-53
-
18
Inoue K, Couch E F, Takano K, Ogawa S.
The structure and function of folliculo-stellate cells in the anterior pituitary gland.
Arch Histol Cytol.
1999;
62
205-218
-
19
Kurotani R, Tahara S, Sanno N et al..
Expression of Ptx1 in the adult rat pituitary glands and pituitary cell lines: hormone-secreting cells and folliculo-stellate cells.
Cell Tissue Res.
1999;
298
55-61
-
20
Yamashita M, Qian Z R, Sano T, Horvath E, Kovacs K.
Immunohistochemical study on so-called follicular cells and folliculostellate cells in the human adenohypophysis.
Pathol Int.
2005;
55
244-247
-
21
Kawakami S, Fujii Y, Okada Y, Winters S J.
Paracrine regulation of FSH by follistatin in folliculostellate cell-enriched primate pituitary cell cultures.
Endocrinology.
2002;
143
2250-2258
-
22
Bergland R M, Torack R M.
An ultrastructural study of follicular cells in the human anterior pituitary.
Am J Pathol.
1969;
57
273-297
-
23
Saez J C, Berthoud V M, Branes M C, Martinez A D, Beyer E C.
Plasma membrane channels formed by connexins: their regulation and functions.
Physiol Rev.
2003;
83
1359-1400
-
24
Fauquier T, Guerineau N C, McKinney R A, Bauer K, Mollard P.
Folliculostellate cell network: a route for long-distance communication in the anterior pituitary.
Proc Natl Acad Sci USA.
2001;
98
8891-8896
-
25
Evans W H, De Vuyst E, Leybaert L.
The gap junction cellular internet: connexin hemichannels enter the signalling limelight.
Biochem J.
2006;
397
1-14
-
26
Geerts A.
History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.
Semin Liver Dis.
2001;
21
311-335
-
27
Inoue K, Matsumoto H, Koyama C, Shibata K, Nakazato Y, Ito A.
Establishment of a folliculo-stellate-like cell line from a murine thyrotropic pituitary tumor.
Endocrinology.
1992;
131
3110-3116
-
28
Bilezikjian L M, Leal A M, Blount A L, Corrigan A Z, Turnbull A V, Vale W W.
Rat anterior pituitary folliculostellate cells are targets of interleukin-1beta and a major source of intrapituitary follistatin.
Endocrinology.
2003;
144
732-740
-
29
Danila D C, Zhang X, Zhou Y et al..
A human pituitary tumor-derived folliculostellate cell line.
J Clin Endocrinol Metab.
2000;
85
1180-1187
-
30
Lloyd R V, Qian X, Jin L et al..
Analysis of pituitary cells by laser capture microdissection.
Methods Mol Biol.
2005;
293
233-241
-
31
Hentges S, Boyadjieva N, Sarkar D K.
Transforming growth factor-beta3 stimulates lactotrope cell growth by increasing basic fibroblast growth factor from folliculo-stellate cells.
Endocrinology.
2000;
141
859-867
-
32
Kabir N, Chaturvedi K, Liu L S, Sarkar D K.
Transforming growth factor-beta3 increases gap-junctional communication among folliculostellate cells to release basic fibroblast growth factor.
Endocrinology.
2005;
146
4054-4060
-
33
Raber J, O'Shea R D, Bloom F E, Campbell I L.
Modulation of hypothalamic-pituitary-adrenal function by transgenic expression of interleukin-6 in the CNS of mice.
J Neurosci.
1997;
17
9473-9480
-
34
Schwartz J, Ray D W, Perez F M.
Leukemia inhibitory factor as an intrapituitary mediator of ACTH secretion.
Neuroendocrinology.
1999;
69
34-43
-
35
Watanobe H, Yoneda M.
A significant participation of leukemia inhibitory factor in regulating the reproductive function in rats: a novel action of the pleiotropic cytokine.
Biochem Biophys Res Commun.
2001;
282
643-646
-
36
Jones K L, de Kretser D M, Patella S, Phillips D J.
Activin A and follistatin in systemic inflammation.
Mol Cell Endocrinol.
2004;
225
119-125
-
37
Shao L, Frigon Jr N L, Sehy D W et al..
Regulation of production of activin A in human marrow stromal cells and monocytes.
Exp Hematol.
1992;
20
1235-1242
-
38
Kawakami S, Fujii Y, Winters S J.
Follistatin production by skin fibroblasts and its regulation by dexamethasone.
Mol Cell Endocrinol.
2001;
172
157-167
-
39
Welt C K.
Regulation and function of inhibins in the normal menstrual cycle.
Semin Reprod Med.
2004;
22
187-193
-
40
Anawalt B D, Bebb R A, Matsumoto A M et al..
Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction.
J Clin Endocrinol Metab.
1996;
81
3341-3345
-
41
Farnworth P G.
Gonadotrophin secretion revisited. How many ways can FSH leave a gonadotroph?.
J Endocrinol.
1995;
145
387-395
-
42
Uccella S, La Rosa S, Genasetti A, Capella C.
Localization of inhibin/activin subunits in normal pituitary and in pituitary adenomas.
Pituitary.
2000;
3
131-139
-
43
Mathews L S.
Activin receptors and cellular signaling by the receptor serine kinase family.
Endocr Rev.
1994;
15
310-325
-
44
Hoodless P A, Wrana J L.
Mechanism and function of signaling by the TGF beta superfamily.
Curr Top Microbiol Immunol.
1998;
228
235-272
-
45
Attisano L, Wrana J L.
Mads and Smads in TGF beta signalling.
Curr Opin Cell Biol.
1998;
10
188-194
-
46
Massague J, Chen Y G.
Controlling TGF-beta signaling.
Genes Dev.
2000;
14
627-644
-
47
Lewis K A, Gray P C, Blount A L et al..
Betaglycan binds inhibin and can mediate functional antagonism of activin signalling.
Nature.
2000;
404
411-414
-
48
Phillips D J, de Kretser D M.
Follistatin: a multifunctional regulatory protein.
Front Neuroendocrinol.
1998;
19
287-322
-
49
Lee B L, Unabia G, Childs G.
Expression of follistatin mRNA by somatotropes and mammotropes early in the rat estrous cycle.
J Histochem Cytochem.
1993;
41
955-960
-
50
Bilezikjian L M, Corrigan A Z, Blount A L, Vale W W.
Pituitary follistatin and inhibin subunit messenger ribonucleic acid levels are differentially regulated by local and hormonal factors.
Endocrinology.
1996;
137
4277-4284
-
51
Kaiser U B, Chin W W.
Regulation of follistatin messenger ribonucleic acid levels in the rat pituitary.
J Clin Invest.
1993;
91
2523-2531
-
52
Dalkin A C, Haisenleder D J, Gilrain J T, Aylor K, Yasin M, Marshall J C.
Regulation of pituitary follistatin and inhibin/activin subunit messenger ribonucleic acids (mRNAs) in male and female rats: evidence for inhibin regulation of follistatin mRNA in females.
Endocrinology.
1998;
139
2818-2823
-
53
Winters S J, Kawakami S, Sahu A, Plant T M.
Pituitary follistatin and activin gene expression, and the testicular regulation of FSH in the adult Rhesus monkey (Macaca mulatta).
Endocrinology.
2001;
142
2874-2878
-
54
Arimura A, Shioda S.
Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptors: neuroendocrine and endocrine interaction.
Front Neuroendocrinol.
1995;
16
53-88
-
55
Culler M D, Paschall C S.
Pituitary adenylate cyclase-activating polypeptide (PACAP) potentiates the gonadotropin-releasing activity of luteinizing hormone-releasing hormone.
Endocrinology.
1991;
129
2260-2262
-
56
Tsujii T, Attardi B, Winters S J.
Regulation of alpha-subunit mRNA transcripts by pituitary adenylate cyclase-activating polypeptide (PACAP) in pituitary cell cultures and alpha T3-1 cells.
Mol Cell Endocrinol.
1995;
113
123-130
-
57
Winters S J, Dalkin A C, Tsujii T.
Evidence that pituitary adenylate cyclase activating polypeptide suppresses follicle-stimulating hormone-beta messenger ribonucleic acid levels by stimulating follistatin gene transcription.
Endocrinology.
1997;
138
4324-4329
-
58
Attardi B, Winters S J.
Transcriptional regulation of the glycoprotein hormone alpha-subunit gene by pituitary adenylate cyclase-activating polypeptide (PACAP) in alphaT3-1 cells.
Mol Cell Endocrinol.
1998;
137
97-107
-
59
Moore Jr J P, Burger L L, Dalkin A C, Winters S J.
Pituitary adenylate cyclase activating polypeptide messenger RNA in the paraventricular nucleus and anterior pituitary during the rat estrous cycle.
Biol Reprod.
2005;
73
491-499
-
60
Arimura A, Somogyvari-Vigh A, Miyata A, Mizuno K, Coy D H, Kitada C.
Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes.
Endocrinology.
1991;
129
2787-2789
-
61
Moore Jr J P, Wilson L, Dalkin A C, Winters S J.
Differential expression of the pituitary gonadotropin subunit genes during male rat sexual maturation: reciprocal relationship between hypothalamic pituitary adenylate cyclase-activating polypeptide and follicle-stimulating hormone beta expression.
Biol Reprod.
2003;
69
234-241
Stephen J Winters
Division of Endocrinology, Metabolism and Diabetes, ACB-A3G11
550 Jackson Street, Louisville, KY 40202
eMail: sjwint01@louisville.edu
