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Updated: Apr 19, 2026
Determining the Role of Maternally-Expressed Genes in Early Development with Maternal Crispants
Published on: December 21, 2021
Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats
Takahiro Nemoto1, Yoshihiko Kakinuma2, Tamotsu Shibasaki2
1Department of PhysiologyNippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan taknemo@nms.ac.jp.
Insights
Low birth weight (LBW) offspring exhibit prolonged hypothalamic-pituitary-adrenal (HPA) axis activation due to impaired miR449a expression, leading to increased stress responses later in life.
Area of Science:
- Endocrinology
- Developmental Biology
- Neuroscience
Background:
- Low birth weight (LBW) is linked to cardiovascular, metabolic, and psychological disorders.
- Maternal malnutrition may program fetal hypothalamic-pituitary-adrenal (HPA) axis function, but mechanisms are unclear.
Purpose of the Study:
- Investigate the mechanisms behind HPA axis programming in LBW offspring.
- Determine the role of miR449a and GAS5 in HPA axis regulation in LBW offspring.
Main Methods:
- Compared HPA axis activity, corticosterone levels, and gene expression (miR449a, Crhr1, GAS5, GR) in LBW and normal-birth-weight (NBW) offspring under restraint stress.
- Analyzed diurnal variations and serum exosomal miR449a content.
Main Results:
- LBW offspring showed elevated plasma corticosterone and impaired corticotropin-releasing factor receptor type 1 (CRF-R1) downregulation.
- miR449a expression was reduced in LBW offspring, associated with increased GAS5 levels.
- Glucocorticoid receptor (GR) downregulation was absent in restrained LBW offspring.
Conclusions:
- Impaired miR449a expression, potentially due to elevated GAS5, disrupts Crhr1 regulation in the anterior pituitary.
- This leads to dysregulated HPA axis activation in LBW offspring, contributing to long-term health risks.
Abstract:
Low birth weight (LBW) is related to increased incidence of common cardiovascular and metabolic disorders, and psychopathologies later in life. Recent studies have suggested that maternal malnutrition affects fetal hypothalamic-pituitary-adrenal (HPA) axis programing although the mechanism is unknown. We demonstrated that LBW offspring delivered from malnourished dams showed prolonged elevated plasma corticosterone concentrations when compared with those of normal-birth-weight (NBW) offspring and impaired downregulation of corticotropin-releasing factor receptor type 1 (CRF-R1, Crhr1) in the anterior pituitary in restraint. Restraint increased expression of miR449a, which we had previously demonstrated to be involved in Crhr1 downregulation, in the anterior pituitary and serum exosomal miR449a contents through glucocorticoids in NBW offspring, but not in LBW offspring. Although plasma corticosterone concentrations were higher at 2000 h than at 0800 h in both LBW and NBW offspring, they were significantly higher in LBW offspring than in NBW offspring at 2000 and 0200 h. There were no significant diurnal changes in miR449a expression levels in the anterior pituitary of either NBW or LBW offspring, but the expression was significantly lower in LBW offspring than in NBW offspring at 1400, 2000, and 0200 h. The expression levels of GAS5, which inhibits glucocorticoid receptor (GR) binding to glucocorticoid-responsive element, in the anterior pituitary of LBW offspring were elevated when compared with those of NBW offspring. The downregulation of GR found in NBW offspring did not occur in restrained LBW offspring. These results indicate that impaired miR449a expression, probably induced by increased GAS5 expression, causes dysregulation of Crhr1 expression in the anterior pituitary, resulting in prolonged HPA axis activation in restrained LBW offspring.
