title: Embryonic epithelial Pten deletion through Nkx2.1-cre leads to thyroid tumorigenesis in a strain-dependent manner.
abstract: Even though the role of the tyrosine phosphatase Pten as a tumor suppressor gene has been well established in thyroid cancer, its role during thyroid development is still elusive. We therefore targeted Pten deletion in the thyroid epithelium by crossing Pten(flox/flox) with a newly developed Nkx2.1-cre driver line in the BALB/c and C57BL/6 genetic backgrounds. C57BL/6 homozygous Pten mutant mice died around 2 weeks of age due to tracheal and esophageal compression by a hyperplasic thyroid. By contrast, BALB/c homozygous Pten mutant mice survived up to 2 years, but with a slightly increased thyroid volume. Characterization of the thyroid glands from C57BL/6 homozygous Pten mutant mice at postnatal day 14 (PN14) showed abnormally enlarged tissue with areas of cellular hyperplasia, disruption of the normal architecture, and follicular degeneration. In addition, differing degrees of hypothyroidism, thyroxine (T(4)) decrease, and thyroid-stimulating hormone elevation between the strains in the mutants and the heterozygous mutant were detected at PN14. Finally, C57BL/6 heterozygous Pten mutant mice developed thyroid tumors after 2 years of age. Our results indicate that Pten has a pivotal role in thyroid development and its deletion results in thyroid tumor formation, with the timing and severity of the tumor depending on the particular genetic background.
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.|Department of Pediatrics, University of Southern California, Los Angeles, California 90027, USA.|Department of Pediatrics, Nassau University Medical Center, 201 Hempstead Turnpike, East Meadow, New York 11554, USA.
authors.forename: Caterina
authors.initials: C
authors.lastname: Tiozzo
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Soula
authors.initials: S
authors.lastname: Danopoulos
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Lavarreda-Pearce
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Baptista
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Radka
authors.initials: R
authors.lastname: Varimezova
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Al Alam
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.affiliation: Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Virender
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80206, USA.
authors.forename: Stijn
authors.initials: S
authors.lastname: De Langhe
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Cristofano
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.|Department of Internal Medicine II, Excellence Cluster Cardio-Pulmonary System, University of Giessen Lung Center, Klinikstrasse 36, Aulweg 130, 35392 Giessen, Germany.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.affiliation: Developmental Biology Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California 90027, USA.|Department of Pediatrics, University of Southern California, Los Angeles, California 90027, USA.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006651:Histocytochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013961:Thyroid Gland / Q000196:embryology* / Q000201:enzymology / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D012313:RNA; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse