Forkhead Box, Class O Transcription Factors in Brain: Regulation and Behavioral Manifestation

Polter, Abigail M.; Yang, Shibing; Zmijewska, Anna A.; Groen, Thomas van; Paik, Ji Hye; DePinho, Ronald A.; Peng, Stanford L.; Jope, Richard S.; Li, Xiaohua

doi:10.1016/j.biopsych.2008.08.005

Cited by 109 publications

(113 citation statements)

References 78 publications

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“…It has been previously reported that Foxo1 is expressed in different tissues, such as brain (28), heart (29,30), liver (29,30), lung (31,32), muscle (33), and fat (18). Here, we show that, during embryonic development, Foxo1 is expressed at its highest level in the areas of intramembranous bone formation, such as calvaria, and endochondral bone formation, such as the diaphysis of long bones.…”

Section: Discussionsupporting

confidence: 63%

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Teixeira

Liu

Thant

et al. 2010

Journal of Biological Chemistry

121

120

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Skeletogenesis depends on the activity of bone-forming cells derived from mesenchymal cells. The pathways that control mesenchymal cell differentiation are not well understood. We propose that Foxo1 is an early molecular regulator during mesenchymal cell differentiation into osteoblasts. In mouse embryos, Foxo1 expression is higher in skeletal tissues, while Foxo1 silencing has a drastic impact on skeletogenesis and craniofacial development, specially affecting pre-maxilla, nasal bone, mandible, tibia, and clavicle. Similarly, Foxo1 activity and expression increase in mouse mesenchymal cells under the influence of osteogenic stimulants. In addition, silencing Foxo1 blocks the expression of osteogenic markers such as Runx2, alkaline phosphatase, and osteocalcin and results in decreased culture calcification even in the presence of strong osteogenic stimulants. Conversely, the expression of these markers increases significantly in response to Foxo1 overexpression. One mechanism through which Foxo1 affects mesenchymal cell differentiation into osteoblasts is through regulation of a key osteogenic transcription factor, Runx2. Indeed, our results show that Foxo1 directly interacts with the promoter of Runx2 and regulates its expression. Using a tibia organ culture model, we confirmed that silencing Foxo1 decreases the expression of Runx2 and impairs bone formation. Furthermore, our data reveals that Runx2 and Foxo1 interact with each other and cooperate in the transcriptional regulation of osteoblast markers. In conclusion, our in vitro, ex vivo, and in vivo results strongly support the notion that Foxo1 is an early molecular regulator in the differentiation of mesenchymal cells into osteoblast.Undifferentiated mesenchymal cells can differentiate into osteoblasts (bone-forming cells), adipocytes (fat cells), chondrocytes (cartilage cells), and myocytes (muscle cells) under the influence of various hormones and growth factors (1). Commitment and differentiation of mesenchymal cells into osteoblasts is crucial during skeletal development and bone growth.Whether mesenchymal cells differentiate along the osteogenic or other pathway depends on the activation of specific transcription factors. The importance of transcription factors in controlling skeletal development can be appreciated in the human skeletal disorder cleidocranial dysplasia. In this condition, deregulation of an important osteogenic transcription factor, Runx2, produces a striking phenotype with anterior fontanelle, hypoplasia or aplasia of the clavicle, wide pubic symphysis, and short stature (2).Although some of the transcription factors that control osteoblast differentiation are well characterized, the role of others remains unclear. One such factor is Foxo1 (forkhead box class O). Foxo1 belongs to the winged helix/forkhead family of transcription factors that is characterized by a 100-amino acid monomeric DNA-binding domain called the FOX domain. Other portions of the forkhead proteins, such as the DNA transactivation or DNA transrepression domains, a...

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Section: Discussionsupporting

confidence: 63%

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Teixeira

Liu

Thant

et al. 2010

Journal of Biological Chemistry

121

120

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“…Recent discoveries indicate a role for FoxO in the pathogenesis of depression and other psychiatric disorders (Polter et al, 2009;Weeks et al, 2010;Zheng et al, 2013). Enhanced neurotrophins or serotonin neurotransmission in animal brain phosphorylate and inactivate FoxO3a (Zheng et al, 2002;Polter et al, 2009).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Forkhead box O transcription factors as possible mediators in the development of major depression

et al. 2015

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“…Until this study, very little was known about the program of gene expression and the role of other FoxO family members in cognition. To date, mice with a specific deletion of FoxO1 in the brain and mice null for FoxO3 have been shown to have decreased anxiety-like and decreased depression-like behaviors using open field assessment, the elevated plus maze, and the forced swim test (Polter et al 2009). However, the role of FoxO1 and FoxO3 in learning and memory has never been tested.…”

Section: Role Of Foxo6 Compared With Other Members Of the Foxo Signalmentioning

confidence: 99%

“…In adults, FoxO family members play an important role in neural stem cell self-renewal and fate Renault et al 2009) and in neuronal apoptosis following epileptic seizures (Shinoda et al 2004). At the organismal level, the deletion of FoxO1 or FoxO3 results in reduced anxiety-and depression-like behaviors, respectively (Polter et al 2009). Interestingly, the insulin/ IGF pathway, which regulates FoxO transcription factors, has been found to impact learning and memory in physiological or pathological conditions such as Alzheimer's disease (Cohen et al 2009;Freude et al 2009;Killick et al 2009;Chen et al 2011).…”

mentioning

confidence: 99%

FoxO6 regulates memory consolidation and synaptic function

et al. 2012

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The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.

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Forkhead Box, Class O Transcription Factors in Brain: Regulation and Behavioral Manifestation

Cited by 109 publications

References 78 publications

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Forkhead box O transcription factors as possible mediators in the development of major depression

FoxO6 regulates memory consolidation and synaptic function

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