FOXP1
Forkhead box protein P1 (Mac-1-regulated forkhead) (MFH) [HSPC215]
Publications[править]
Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells but how molecular mechanisms through which reprogrammed cells alter aging-related cellular activities still remain largely unclear. In this study, we reprogrammed human synovial fluid-derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging-related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 (FOXP1), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and FOXP1 pathway to modulate cellular senescence and aging-related activities.
Keywords
- aging
- cell signaling
- mesenchymal stem cells
- reprogramming
- transcription factors
FoxP transcription factors play crucial roles for the development and function of vertebrate brains. In humans the neurally expressed FOXPs, FOXP1, FOXP2, and FOXP4 are implicated in cognition, including language. Neural FoxP expression is specific to particular brain regions but FoxP1, FoxP2 and FoxP4 are not limited to a particular neuron or neurotransmitter type. Motor- or sensory activity can regulate FoxP2 expression, e.g. in the striatal nucleus Area X of songbirds and in the auditory thalamus of mice. The DNA-binding domain of FoxP proteins is highly conserved within metazoa, raising the possibility that cellular functions were preserved across deep evolutionary time. We have previously shown in bee brains that FoxP is expressed in eleven specific neuron populations, seven tightly packed clusters and four loosely arranged groups. The present study examined the co-expression of honeybee FoxP (AmFoxP) with markers for glutamatergic, GABAergic, cholinergic and monoaminergic transmission. We found that AmFoxP could co-occur with any one of those markers. Interestingly, AmFoxP clusters and AmFoxP groups differed with respect to homogeneity of marker co-expression; within a cluster, all neurons co-expressed the same neurotransmitter marker, within a group co-expression varied. We also assessed qualitatively whether age or housing conditions providing different sensory and motor experiences affected the AmFoxP neuron populations, but found no differences. Based on the neurotransmitter homogeneity we conclude that AmFoxP neurons within the clusters might have a common projection and function whereas the AmFoxP groups are more diverse and could be further sub-divided. The obtained information about the neurotransmitters co-expressed in the AmFoxP neuron populations facilitated the search of similar neurons described in the literature. These comparisons revealed e.g. a possible function of AmFoxP neurons in the central complex. Our findings provide opportunities to focus future functional studies on invertebrate FoxP expressing neurons. In a broader context, our data will contribute to the ongoing efforts to discern in which cases relationships between molecular and phenotypic signatures are linked evolutionary.
MeSH Terms
- Aging
- Animals
- Bees
- Brain
- Forkhead Transcription Factors
- In Situ Hybridization
- Insect Proteins
- Neurons
- Neurotransmitter Agents
Keywords
- Acetylcholine
- Deep homology
- FoxP
- FoxP1
- GABA
- Glutamate
- Honeybee
- In situ hybridization
- Monoamine
- Songbird
Aging is known as a major risk factor for tendon disorders whereas the molecular mechanisms of age-related tendon disorders still remains unclear. Since tendon-derived stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and healing, in this study we aimed to investigate the role of Forkhead box P1 (FOXP1) in aged TSPCs, we found that FOXP1 mRNA and protein levels were markedly decreased in the aged TSPCs. Moreover, overexpression of FOXP1 attenuates TSPCs aging, as confirmed by decreased of senescence-associated β-gal staining, as well as the senescence marker, p16 . Conversely, FOXP1 depletion by siRNA promoted senescence in young TSPCs. Meanwhile, FOXP1 overexpression also restores the age-associated reduction of self-renewal, migration and differentiation of TSPCs. In addition, FOXP1 overexpression rescued decreased levels of E2F1, pRb and cyclin D1 in aged TSPCs, which suggested that FOXP1 regulates TSPCs aging through cellular senescence. These results indicate that FOXP1 plays a crucial role in TSPCs aging.
MeSH Terms
- Animals
- Cell Cycle
- Cell Differentiation
- Cell Movement
- Cells, Cultured
- Cellular Senescence
- Down-Regulation
- Forkhead Transcription Factors
- Male
- Rats, Sprague-Dawley
- Repressor Proteins
- Stem Cells
- Tendons
Keywords
- Aging
- Cell cycle
- FOXP1
- Tendon-derived stem/progenitor cells