Abstract
Glucocorticoids (GCs) are a class of steroid hormones that regulate numerous physiological events in the human body. Clinically, glucocorticoids are used for anti-inflammatory and immunosuppressive actions via binding with glucocorticoid receptors (GRs). Emerging evidence has also indicated that inappropriate GC and GR levels are detrimental for brain development and eventually lead to severe neurological diseases. However, the roles of GC/GR signaling in brain development are not fully understood. Here, we showed that stable GR expression levels were critical for brain development, because both GR knockdown and overexpression severely impaired neuronal migration. Further studies showed that the multipolar-bipolar transition and leading process development were interrupted in GR-knockdown and GR-overexpressing neurons. To elucidate the underlying mechanism, we screened the protein levels of downstream molecules and identified RhoA as a factor negatively regulated by the GR. Restoration of the RhoA protein level partially rescued the neuronal migration defects in the GR-knockdown and GR-overexpressing neurons, indicating that RhoA played a major role in GR-mediated neuronal migration. These data suggest that an appropriate level of GC/GR signaling is essential for precise control of neuronal migration.
Highlights
Glucocorticoids (GCs) have profound influences on many physiological functions, including growth, metabolism, development, behaviors and stress reactions (Blodgett et al 1956, Munck et al 1984, Haskett 1985)
Western blotting showed that glucocorticoid receptors (GRs) expression was maintained at a relatively stable level from E13.5 to P7 (Fig. 1A and B), which was consistent with a previous report (Meaney et al 1985)
Costaining for the GR and MAP2, which is a neuron dendritic process marker, revealed that the GR was mainly distributed in the nucleus in the upper intermediate zone (upIZ) and in both the nucleus and cytoplasm in the cortical plate (CP) (Fig. 1C)
Summary
Glucocorticoids (GCs) have profound influences on many physiological functions, including growth, metabolism, development, behaviors and stress reactions (Blodgett et al 1956, Munck et al 1984, Haskett 1985). They exert anti-inflammatory and immunosuppressive effects and are used as therapeutic agents (Coutinho & Chapman 2011). Once bound to GCs, activated cytoplasmic GRs translocate to the nucleus and regulate gene expression through either direct interaction with specific promoter sequences or protein–protein interactions with other transcription factors (Mitre-Aguilar et al 2015). GC/GR signaling-mediated gene expression is clinically significant, excessive exposure to this signal can lead to severe side effects
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