Microglia Rank signaling regulates GnRH neuronal function and the hypothalamic-pituitary-gonadal axis

Area of Science:

• Neuroendocrinology
• Immunology
• Reproductive Biology

Background:

• The hypothalamic-pituitary-gonadal (HPG) axis is crucial for reproductive functions.
• Microglia, the brain's immune cells, are increasingly recognized for their roles beyond immunity.

Purpose of the Study:

• To investigate the role of hypothalamic microglia in regulating the HPG axis.
• To explore the involvement of receptor activator of nuclear factor kappa-B (Rank) signaling in this process.

Main Methods:

• Utilized whole-body and microglia-specific Rank depletion models.
• Performed transcriptional profiling to analyze gene expression changes.
• Examined microglia-neuron interactions in the median eminence.
• Investigated GnRH neuron function and response to kisspeptin.

Main Results:

• Rank depletion in microglia and systemically caused hypogonadotropic hypogonadism (HH).
• Rank loss altered gonadotropin-releasing hormone (GnRH) neuron function and morphology of the median eminence.
• Microglia showed defective activation and reduced engulfment of GnRH neuron terminals.
• Rare variants in the RANK gene were identified in patients with HH.

Conclusions:

• Hypothalamic microglia regulate GnRH neuron function through Rank signaling.
• This pathway is critical for normal reproductive maturation and fertility.
• Dysregulation of microglia- द्वारा Rank signaling may contribute to HH.