Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues.
Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.
Biondi
Christine A
CA
Queensland Institute of Medical Research, Herston, Queensland, Australia.
Gartside
Michael G
MG
Waring
Paul
P
Loffler
Kelly A
KA
Stark
Mitchell S
MS
Magnuson
Mark A
MA
Kay
Graham F
GF
Hayward
Nicholas K
NK
D000818:Animals; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005091:Exons; D005260:Female; D020868:Gene Silencing; D006965:Hyperplasia / Q000473:pathology; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015175:Prolactinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019076:Transgenes; D014764:Viral Proteins / Q000378:metabolism
D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases