SMAD7
Mothers against decapentaplegic homolog 7 (MAD homolog 7) (Mothers against DPP homolog 7) (Mothers against decapentaplegic homolog 8) (MAD homolog 8) (Mothers against DPP homolog 8) (SMAD family member 7) (SMAD 7) (Smad7) (hSMAD7) [MADH7] [MADH8]
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The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in β cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated β cell dysfunction and loss of proliferation capacity, two features of β cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in β cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in β cells prevented β cell dysfunction and loss in this model. Thus, we present a model of accelerated β cell aging that may be useful for studying the mechanisms underlying β cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining β cell identity in the context of SMAD7 failure.
MeSH Terms
- Animals
- Cell Proliferation
- Cellular Senescence
- Diabetes Mellitus
- Forkhead Box Protein O1
- Insulin-Secreting Cells
- Male
- Mice
- Mice, Knockout
- Mice, SCID
- Mutation
- Pancreas
- Protein Transport
- Smad7 Protein
Keywords
- Aging
- FoxO1
- SMAD7
- TGFβ
- cell proliferation
- diabetes
- type 2 diabetes
- β cell
The review presents an overview of studies that examined the effects of follicular aging and maternal aging in the bovine model. The first of three main sections is a discussion of the developmental competence of oocytes from (1) the ovulatory follicle of 2-wave and 3-wave estrous cycles, (2) dominant follicles that develop under high or low LH pulse frequency, and (3) natural versus FSH-stimulated ovulatory follicles. The second section highlights the effects of maternal aging. Maternal aging in cattle is associated with (1) elevated circulating FSH concentrations, (2) reduced response to superstimulatory treatment, and (3) markedly decreased early embryonic development in cows >12 year of age. The third and final section on superstimulation protocols addresses the effects of the duration of FSH stimulation and withdrawal (i.e., FSH "starvation" or "coasting") on oocyte competence. Ovarian superstimulation for 4 days altered the expression of genes related to angiogenesis, and activated oxidative stress-response genes. Extending the duration of FSH stimulation from 4 to 7 days resulted in a greater and more synchronous ovulatory response and optimal oocyte maturation. The highest rates of blastocyst development in vitro were obtained when FSH support was discontinued for 44 to 68h and granulosa cell SMAD7 mRNA was predictive of this period. Longer periods of FSH starvation resulted in a loss of oocyte competence or ovulatory capability. By extending the bovine model to the transcriptome level, new approaches and treatments may be devised to resolve subfertility in women and animals.
MeSH Terms
- Aging
- Animals
- Cattle
- Female
- Granulosa Cells
- Humans
- Oocytes
- Ovulation Induction
- Superovulation
Keywords
- Dominant follicle aging
- FSH starvation
- Granulosa cell function
- Maternal aging
- Oocyte competence
- Superstimulation