Reference SummaryHarding B, Endocr Relat Cancer 2009 Dec;16(4):1313-27

Title

Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia.

Authors

Harding B; Lemos MC; Reed AA; Walls GV; Jeyabalan J; Bowl MR; Tateossian H; Sullivan N; Hough T; Fraser WD; Ansorge O; Cheeseman MT; Thakker RV

Journal

Endocr Relat Cancer

Volume

16

Issue

4

Year

2009

Pages

1313-27

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized in man by parathyroid, pancreatic, pituitary and adrenal tumours. The MEN1 gene encodes a 610-amino acid protein (menin) which is a tumour suppressor. To investigate the in vivo role of menin, we developed a mouse model, by deleting Men1 exons 1 and 2 and investigated this for MEN1-associated tumours and serum abnormalities. Men1(+/-) mice were viable and fertile, and 220 Men1(+/-) and 94 Men1(+/+) mice were studied between the ages of 3 and 21 months. Survival in Men1(+/-) mice was significantly lower than in Men1(+/+) mice (<68% vs >85%, P<0.01). Men1(+/-) mice developed, by 9 months of age, parathyroid hyperplasia, pancreatic tumours which were mostly insulinomas, by 12 months of age, pituitary tumours which were mostly prolactinomas, and by 15 months parathyroid adenomas and adrenal cortical tumours. Loss of heterozygosity and menin expression was demonstrated in the tumours, consistent with a tumour suppressor role for the Men1 gene. Men1(+/-) mice with parathyroid neoplasms were hypercalcaemic and hypophosphataemic, with inappropriately normal serum parathyroid hormone concentrations. Pancreatic and pituitary tumours expressed chromogranin A (CgA), somatostatin receptor type 2 and vascular endothelial growth factor-A. Serum CgA concentrations in Men1(+/-) mice were not elevated. Adrenocortical tumours, which immunostained for 3-beta-hydroxysteroid dehydrogenase, developed in seven Men1(+/-) mice, but resulted in hypercorticosteronaemia in one out of the four mice that were investigated. Thus, these Men1(+/-) mice are representative of MEN1 in man, and will help in investigating molecular mechanisms and treatments for endocrine tumours.

Links

J:191261 – Mouse Genome Informatics
19620250 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129-Men1tm1Rvt/+ Adipose tissue lipoma Adipose tissue

observed

B6;129-Men1tm1Rvt/+ Adrenal gland - Cortex adenoma Adrenal gland - Cortex

observed

B6;129 Adrenal gland - Cortex hyperplasia Adrenal gland - Cortex

observed

B6;129-Men1tm1Rvt/+ Adrenal gland - Cortex hyperplasia Adrenal gland - Cortex

observed

B6;129-Men1tm1Rvt/+ Adrenal gland - Cortex tumor Adrenal gland - Cortex

0 - 16

B6;129-Men1tm1Rvt/+ Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

observed

B6;129 Adrenal gland - Subcapsular cell hyperplasia Adrenal gland - Subcapsular cell

observed

B6;129-Men1tm1Rvt/+ Adrenal gland - Subcapsular cell hyperplasia Adrenal gland - Subcapsular cell

observed

B6;129-Men1tm1Rvt/+ Adrenal gland adenoma Adrenal gland

observed

B6;129 Adrenal gland tumor Adrenal gland

0

B6;129-Men1tm1Rvt/+ Adrenal gland tumor Adrenal gland

observed

B6;129 Gonad (sex not specified) tumor Gonad (sex not specified)

0

B6;129-Men1tm1Rvt/+ Intestine - Small Intestine - Duodenum - Proximal tumor - neuroendocrine Intestine - Small Intestine - Duodenum - Proximal

0

B6;129 Lung adenoma Lung

observed

B6;129-Men1tm1Rvt/+ Ovary - Germ cell dysgerminoma Ovary - Germ cell

observed

B6;129-Men1tm1Rvt/+ Ovary - Granulosa cell tumor Ovary - Granulosa cell

observed

B6;129-Men1tm1Rvt/+ Ovary - Sex cord stromal cell tumor Ovary - Sex cord stromal cell

observed

B6;129 Ovary cyst Ovary

observed

B6;129-Men1tm1Rvt/+ Ovary luteoma Ovary

observed

B6;129 Ovary tumor Ovary

0

B6;129-Men1tm1Rvt/+ Ovary tumor Ovary

40

B6;129-Men1tm1Rvt/+ Ovary tumor - tubulostromal Ovary

observed

B6;129-Men1tm1Rvt/+ Pancreas - Islet of Langerhans - Beta cell insulinoma Pancreas - Islet of Langerhans - Beta cell

observed

B6;129-Men1tm1Rvt/+ Pancreas - Islet of Langerhans adenoma Pancreas - Islet of Langerhans

60%

B6;129-Men1tm1Rvt/+ Pancreas - Islet of Langerhans gastrinoma Pancreas - Islet of Langerhans

0

B6;129-Men1tm1Rvt/+ Pancreas - Islet of Langerhans hyperplasia Pancreas - Islet of Langerhans

observed

B6;129-Men1tm1Rvt/+ Pancreas - Islet of Langerhans neoplasia Pancreas - Islet of Langerhans

observed

B6;129-Men1tm1Rvt/+ Pancreas - Islet of Langerhans tumor Pancreas - Islet of Langerhans

60% - 57

B6;129 Pancreas tumor Pancreas

0

B6;129-Men1tm1Rvt/+ Parathyroid gland adenoma Parathyroid gland

25 - 26

B6;129-Men1tm1Rvt/+ Parathyroid gland adenoma - papillary Parathyroid gland

observed

B6;129-Men1tm1Rvt/+ Parathyroid gland hyperplasia - focal Parathyroid gland

60

B6;129-Men1tm1Rvt/+ Parathyroid gland hyperplasia - nodular Parathyroid gland

observed

B6;129-Men1tm1Rvt/+ Parathyroid gland lesion Parathyroid gland

85

B6;129 Parathyroid gland tumor Parathyroid gland

0

B6;129-Men1tm1Rvt/+ Parathyroid gland tumor Parathyroid gland

40 - 85

B6;129 Peritoneum - Mesentery sarcoma - spindle cell - anaplastic Peritoneum - Mesentery

observed

B6;129-Men1tm1Rvt/+ Pituitary gland - Anterior adenoma - macroadenoma Pituitary gland - Anterior

observed

B6;129-Men1tm1Rvt/+ Pituitary gland - Anterior prolactinoma Pituitary gland - Anterior

observed

B6;129-Men1tm1Rvt/+ Pituitary gland - Anterior somatolactotrophinoma Pituitary gland - Anterior

observed

B6;129-Men1tm1Rvt/+ Pituitary gland - Anterior tumor Pituitary gland - Anterior

35

B6;129-Men1tm1Rvt/+ Pituitary gland - Pars distalis tumor Pituitary gland - Pars distalis

observed

B6;129-Men1tm1Rvt/+ Pituitary gland - Pars intermedia tumor Pituitary gland - Pars intermedia

observed

B6;129-Men1tm1Rvt/+ Pituitary gland - Pars nervosa tumor Pituitary gland - Pars nervosa

0

B6;129-Men1tm1Rvt/+ Pituitary gland adenoma Pituitary gland

observed

B6;129-Men1tm1Rvt/+ Pituitary gland adenoma - macroadenoma Pituitary gland

observed

B6;129 Pituitary gland hyperplasia - focal Pituitary gland

observed

B6;129-Men1tm1Rvt/+ Pituitary gland hyperplasia - focal Pituitary gland

observed

B6;129 Pituitary gland tumor Pituitary gland

0

B6;129-Men1tm1Rvt/+ Pituitary gland tumor Pituitary gland

3.9 - 43

B6;129-Men1tm1Rvt/+ Stomach tumor - neuroendocrine Stomach

0

B6;129 Testis - Leydig cell (Interstitial cell) hyperplasia Testis - Leydig cell (Interstitial cell)

0

B6;129-Men1tm1Rvt/+ Testis - Leydig cell (Interstitial cell) hyperplasia Testis - Leydig cell (Interstitial cell)

45

B6;129-Men1tm1Rvt/+ Testis - Leydig cell (Interstitial cell) tumor Testis - Leydig cell (Interstitial cell)

60

B6;129-Men1tm1Rvt/+ Testis - Leydig cell (Interstitial cell) tumor - malignant Testis - Leydig cell (Interstitial cell)

observed

B6;129-Men1tm1Rvt/+ Testis teratoma Testis

1.3

B6;129 Testis tumor Testis

0

B6;129-Men1tm1Rvt/+ Testis tumor Testis

65

B6;129-Men1tm1Rvt/+ Thyroid gland - Follicular cell adenoma Thyroid gland - Follicular cell

10

B6;129-Men1tm1Rvt/+ Thyroid gland - Medulla - C cell adenoma Thyroid gland - Medulla - C cell

5

B6;129-Men1tm1Rvt/+ Thyroid gland adenoma Thyroid gland

15

B6;129 Thyroid gland tumor Thyroid gland

0

B6;129 Uterus - Endometrium hyperplasia - cystic Uterus - Endometrium

observed

B6;129 (Unspecified organ) lesion (Unspecified organ)

0 - observed

B6;129-Men1tm1Rvt/+ (Unspecified organ) tumor (Unspecified organ)

5 - 84