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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Genetics

Much of what is known about the effects of FOXO3 mutation has been discovered using Foxo3a-/- mice. Like Foxo4-/-, these mice are viable, unlike Foxo1-/- mice which die at embryonic day 10.5 [1]. There is redundancy between the FoxO members, hence loss of Foxo3a does not show a particularly strong phenotype. Foxo3a-/- mice show widespread organ inflammation, particularly of the salivary gland, lung, and kidney, as well as lymphoproliferation and lymphadenopathy. This is probably caused by the T helper cell hyperactivation also seen in these mice, resulting from increased NFκB activity. In normal cells, Foxo3a inhibits NFκB activity by indirectly upregulating expression of IκB family members (inhibitor of NFκB) that sequester it in the cytoplasm [2]. Foxo3a-/- mice are also mildly anaemic, and may have impaired glucose tolerance compared to controls [3].

Female Foxo3a-/- mice have a further phenotype of an age-dependent reduction in fertility, resulting in complete infertility by 10-15 weeks of age. This is due to excessive follicular activation (even before sexual maturity) and thus depletion, as well as oocyte loss [3][4]. Although this infertility resembles the human condition primary ovarian insufficiency (POI), polymorphisms in FOXO3a are not thought to be directly connected to POI [5].

FOXO3 polymorphisms have, however, been linked to other human phenotypes. A study of long-lived Japanese males linked three FOXO3 SNPs with longevity. One of the SNPs in particular was also linked to a reduction in age-related diseases [6]. Another SNP in a Korean population, in the promoter region of FOXO3a, was associated with body mass index [7].

References
  1. Arden KC. FOXO animal models reveal a variety of diverse roles for FOXO transcription factors. Oncogene, 27(16):2345-50. (PMID 18391976)
  2. Lin L et al. Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity, 21(2):203-13. (PMID 15308101)
  3. Castrillon DH et al. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science, 301(5630):215-8. (PMID 12855809)
  4. Hosaka T et al. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl. Acad. Sci. U.S.A., 101(9):2975-80. (PMID 14978268)
  1. Watkins WJ et al. Mutational screening of FOXO3A and FOXO1A in women with premature ovarian failure. Fertil. Steril., 86(5):1518-21. (PMID 16979636)
  2. Willcox BJ et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl. Acad. Sci. U.S.A., 105(37):13987-92. (PMID 18765803)
  3. Kim JR et al. Polymorphisms in FOXO gene family and association analysis with BMI. Obesity (Silver Spring), 14(2):188-93. (PMID 16571842)
MeSH cloud (automatically populated)
About this section
The MeSH cloud below displays MeSH terms that are associated with this transcription factor. The physical size of the terms reflect the significance of their association with the transcription factor as determined by the Fisher's Exact Test. It should be noted that these associations do not necessarily imply a positive correlation between the described MeSH term and this transcription factor. For instance, if the MeSH term "apoptosis" occurs, it may indicate that this transcription factor can induce apoptosis (positive correlation), or prevent apoptosis (negative correlation). Methods: The transcription factor is mapped to a set of Pubmed publications through the gene-to-pubmed association as provided by NCBI. Then, a collection of MeSH terms associated with the papers are compiled, along with the frequency of each MeSH term. The Fisher's Exact Test is conducted on the frequency of each term in the collection, versus its average frequency, to determine its significance in the collection. More information on MeSH can be found on the MeSH homepage.
MeSH term Fisher's exact p-value
1 Prostatic Neoplasms 3.7 x 10-8
2 Ovarian Failure, Premature 7.4 x 10-8
3 Neuroblastoma 5.0 x 10-7
4 Cell Transformation, Neoplastic 3.0 x 10-6
5 Genetic Predisposition to Disease 0.00054
6 Papilloma, Intraductal 0.0016
7 Atherosclerosis 0.0021
8 Rhabdomyosarcoma, Alveolar 0.0029
9 Leukemia, Myelogenous, Chronic, BCR-ABL Positive 0.0034
10 HIV-Associated Lipodystrophy Syndrome 0.0055
11 Fibroadenoma 0.0084
12 Translocation, Genetic 0.010
13 Hyperplasia 0.014
14 Disease Progression 0.017
15 Insulin Resistance 0.022
16 Carotid Artery Injuries 0.024
17 Neoplasm Invasiveness 0.031
18 Neoplasms, Hormone-Dependent 0.031
19 Neoplasm, Residual 0.032
20 Hematologic Neoplasms 0.043
MeSH term Fisher's exact p-value
1 Neoplasms 1.1 x 10-11
2 Breast Neoplasms 3.7 x 10-8
3 Prostatic Neoplasms 3.7 x 10-8
4 Ovarian Failure, Premature 7.4 x 10-8
5 Breast Diseases 7.8 x 10-8
6 Prostatic Diseases 1.8 x 10-7
7 Genital Neoplasms, Male 3.8 x 10-7
8 Neoplastic Processes 4.6 x 10-7
9 Neuroblastoma 5.0 x 10-7
10 Neuroectodermal Tumors, Primitive, Peripheral 6.7 x 10-7
11 Neoplasms by Site 1.7 x 10-6
12 Neuroectodermal Tumors, Primitive 1.8 x 10-6
13 Cell Transformation, Neoplastic 3.0 x 10-6
14 Neoplasms, Neuroepithelial 1.8 x 10-5
15 Genital Diseases, Male 0.00023
16 Neuroectodermal Tumors 0.00037
17 Urogenital Neoplasms 0.00047
18 Genetic Predisposition to Disease 0.00054
19 Neoplasms, Nerve Tissue 0.00068
20 Skin Diseases 0.00088
21 Neoplasms, Germ Cell and Embryonal 0.0011
22 Neoplasms by Histologic Type 0.0012
23 Myeloproliferative Disorders 0.0015
24 Ovarian Diseases 0.0015
25 Papilloma, Intraductal 0.0016
26 Disease Susceptibility 0.0016
27 Atherosclerosis 0.0021
28 Adnexal Diseases 0.0027
29 Rhabdomyosarcoma, Alveolar 0.0029
30 Leukemia, Myelogenous, Chronic, BCR-ABL Positive 0.0034
31 Neoplasms, Glandular and Epithelial 0.0047
32 HIV-Associated Lipodystrophy Syndrome 0.0055
33 Skin and Connective Tissue Diseases 0.0061
34 DNA Damage 0.0065
35 Fibroadenoma 0.0084
36 Bone Marrow Diseases 0.0092
37 Translocation, Genetic 0.010
38 Gonadal Disorders 0.011
39 Hyperplasia 0.014
40 Disease Progression 0.017
41 Pathologic Processes 0.021
42 Insulin Resistance 0.022
43 Gastrointestinal Neoplasms 0.022
44 Lipodystrophy 0.022
45 Carotid Artery Injuries 0.024
46 Neoplasms, Fibroepithelial 0.026
47 Cerebrovascular Trauma 0.027
48 Hyperinsulinism 0.028
49 Neoplasm Invasiveness 0.031
50 Neoplasms, Hormone-Dependent 0.031
51 Neoplasm, Residual 0.032
52 Leukemia 0.033
53 Sexually Transmitted Diseases, Viral 0.040
54 HIV Infections 0.042
55 Hematologic Neoplasms 0.043
56 Lentivirus Infections 0.044
MGI mammalian phenotype terms (automatically populated)
premature death (MP:0002083) abnormal estrous cycle (MP:0001927) increased tumor incidence (MP:0002020) dermatitis (MP:0001194) abnormal oocyte morphology (MP:0001125) female infertility (MP:0001926) reduced female fertility (MP:0001923) anemia (MP:0001577) hemolytic anemia (MP:0001585) abnormal ovarian folliculogenesis (MP:0001130) increased circulating follicle stimulating hormone level (MP:0001750) increased circulating luteinizing hormone level (MP:0001751) reticulocytosis (MP:0002640) impaired glucose tolerance (MP:0005293) prolactinoma (MP:0003505) hemangiosarcoma (MP:0003667) enlarged ovary (MP:0004832) absent estrous cycle (MP:0009009) impaired ovarian folliculogenesis (MP:0001129) decreased mature ovarian follicle number (MP:0002682) oocyte degeneration (MP:0009093) increased inflammatory response (MP:0001846) abnormal T cell physiology (MP:0002444) kidney inflammation (MP:0001859) salivary gland inflammation (MP:0001870) enlarged lymph nodes (MP:0000702) enlarged spleen (MP:0000691) spleen hyperplasia (MP:0000693) lymphoid hyperplasia (MP:0000688) abnormal T cell activation (MP:0001828) lung inflammation (MP:0001861) abnormal immune system organ morphology (MP:0002722) increased T cell proliferation (MP:0005348) lung adenoma (MP:0002048) pituitary adenoma (MP:0002041) teratoma (MP:0002627) thymic lymphoma (MP:0005234) hemangioma (MP:0002947) hamartoma (MP:0006381) abnormal blood vessel morphology (MP:0001614) hepatic hemangioma (MP:0002047) abnormal NK cell morphology (MP:0005068) decreased apoptosis (MP:0006043) increased NK cell number (MP:0008044) decreased physiological sensitivity to xenobiotic (MP:0008874) increased mean corpuscular volume (MP:0002590) decreased erythrocyte cell number (MP:0002875) increased mean corpuscular hemoglobin (MP:0005561) abnormal hematopoietic stem cell morphology (MP:0004808) decreased hematopoietic stem cell number (MP:0004810) increased sensitivity to xenobiotic induced morbidity/mortality (MP:0009766)