Mild pituitary phenotype in 3- and 12-month-old Aip-deficient male mice.
Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip(+/-)) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip(+/-) mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip(+/-) mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip(+/-) mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip(+/-) mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip(+/-) mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip(+/-) mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model.
Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Anne-Lise
AL
Lecoq
Inserm U894Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Philippe
P
Zizzari
Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Mirella
M
Hage
Sorbonne UniversitésUniv Paris 06 UMRS 938, Inserm U938, CDR Saint-Antoine, Paris, France.
Lyvianne
L
Decourtye
Assistance Publique-Hôpitaux de ParisService d'Anatomie et Cytologie Pathologiques, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Clovis
C
Adam
Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Say
S
Viengchareun
Department of MedicineEndocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota, USA.
Johannes D
JD
Veldhuis
Inserm U1132Hôpital Lariboisière, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Valérie
V
Geoffroy
Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Marc
M
Lombès
Inserm U894Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Virginie
V
Tolle
Unité Mixte de Recherche-5203Centre National de la Recherche Scientifique, Institut de Génomique Fonctionnelle, Montpellier, France.
Anne
A
Guillou
Department of Medical GeneticsGenome-Scale Biology Research Program Biomedicum, University of Helsinki, Helsinki, Finland.
Auli
A
Karhu
Sorbonne UniversitésUniv Paris 06 UMRS 938, Inserm U938, CDR Saint-Antoine, Paris, France.
Laurent
L
Kappeler
Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
Philippe
P
Chanson
Institut National de la Santé et de la Recherche Médicale (Inserm) U1185Le Kremlin-Bicêtre, France Université Paris-SudFaculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France Assistance Publique-Hôpitaux de ParisService d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin Bicêtre, France peter.kamenicky@bct.aphp.fr.
Peter
P
Kamenický
D000236:Adenoma / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D013006:Growth Hormone / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D010641:Phenotype; D010902:Pituitary Gland / Q000166:cytology / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics*; D052683:Somatotrophs / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
AIP; aryl hydrocarbon receptor-interacting protein; germline mutations; growth hormone; pituitary adenoma