Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse

Area of Science:

• Reproductive biology
• Molecular endocrinology
• Developmental biology

Background:

• Extracellular-signal-regulated kinases (ERK) 1 and 2 are key regulators of the hypothalamic-pituitary-gonadal axis.
• The specific role of ERK1/2 signaling within the implantation site, particularly in decidual cells, remains largely unexplored.

Purpose of the Study:

• To investigate the function of ERK1/2 signaling in GnRH receptor (GnRHR)-expressing cells during pregnancy.
• To determine the impact of impaired ERK1/2 signaling on placental development, parturition, and neonatal outcomes.

Main Methods:

• Generation of GRIC-ERKdko mice with conditional knockout of ERK1/2 in GnRHR-expressing cells.
• Assessment of reproductive parameters, including fertility, litter size, and pup survival.
• Analysis of placental architecture, ERK2 expression, and apoptotic events via histopathology.
• Quantification of GnRHR mRNA levels in pituitary and implantation sites.

Main Results:

• GRIC-ERKdko females exhibited hypogonadotropic, anovulatory phenotypes and reduced fertility.
• Placentas from GRIC-ERKdko mice displayed reduced ERK2 expression and abnormal architecture.
• Impaired ERK signaling led to delayed parturition, reduced pup weights, and 100% neonatal mortality.
• Apoptotic activity at the decidual-uterine interface was significantly reduced in GRIC-ERKdko animals.

Conclusions:

• ERK1/2 signaling within the implantation site is essential for normal placental development and function.
• Disruption of ERK signaling contributes to pregnancy complications, including prolonged gestation and neonatal death.
• These findings highlight a critical role for ERK-dependent pathways in regulating parturition and ensuring neonatal survival.