Caldesmon,an actin-linked regulatory protein,comes across glucocorticoids

The glucocorticoids (GCs), the most downstream effectors of the hypothalamic-pituitary-adrenal (HPA) axis, are the main mediators of stress response. Stress-triggered GCs as well as acute and chronic GC treatment can impair the structural plasticity and function of the brain. The exposure of perinatal animals and humans to excess stress or GCs can affect the brain development, resulting in altered behaviors in the adult offspring of animals and an increased risk of psychiatric disorders in humans. Despite the numerous studies documenting these effects, the underlying mechanism remains unclear. In this commentary we will focus on the effect of excess GCs on cortical development. We have recently showed that excess-GC-dependent retardation of the radial migration of neural progenitor cells (NPCs) is caused by the dysregulation of actin-myosin interaction via upregulation of caldesmon (CaD), an actin-linked regulatory protein. The elucidation of the molecular mechanisms that underlie the detrimental action of GCs on cortical development will expand our understanding of how stress/GCs alter the formation of neural networks and affect behaviors later in life.Key words: neuronal migration, actin-myosin interaction, cortical development, stress, psychiatric disorderIt has been well documented that the elevation of GCs in response to stress impairs the development and function of the brain.^1–3 Prenatal stress is associated with an increase in abnormal behaviors of adult offspring.² In humans, maternal stress increases the risk of psychiatric disorders, including anxiety, depression and schizophrenia, in the offspring during adolescence and adulthood.^3–6 The treatment of neonatal rats with GC transiently retards their brain development,^3,5,7 and giving GC to pregnant sheep retards fetal brain growth.⁸ Antenatal exposure to synthetic GC in humans results in a reduced cortex convolution index and surface area in infants.⁹ Thus, excessive stress or GC exposure during the perinatal stages affects the brain development and subsequently causes abnormal behaviors in experimental animals and an increased incidence of psychiatric disorders in humans. Despite the numerous studies documenting these detrimental effects of GCs, the underlying mechanism remains unclear.Cortical development progresses by two types of neuronal migration: radial and tangential.^10,11 Postmitotic NPCs in the ventricular zone (VZ) migrate radially along radial glial fibers toward the surface of the neocortex, until they reach their final destination within the cortical plate (CP). About 80–90% of all cortical neurons arise from NPCs by radial migration. The remaining cells, which include the majority of GABAergic interneurons, migrate tangentially from the ganglionic eminence to the neocortex. Several human disorders that arise from defective neuronal migration have been identified. These disorders include periventricular nodular heterotopia and lissencephaly, which are caused by mutations in the genes involved in radial migration.¹² More commonly than gene mutations, however, environmental factors such as stress-triggered GCs as described above are implicated in inducing abnormalities in brain development. Most recently, we have found that excess GCs cause a change in radial migration during cortical development via the dysregulation of actomyosin system by GC-induced upregulation of CaD.¹³