[Elucidating the Pathophysiology of Various Diseases by Investigating the Role of Molecules in Brain Wiring]

Semaphorins and their receptors plexins are axon guidance molecules that navigate axons to their final destinations during neural development. Semaphorins and plexins exert distinct roles in regulating biological functions such as the immune system and bone homeostasis. They also participate in the development and progression of various diseases such as osteoporosis and allergic diseases. This review describes the varied phenotypes revealed by the analysis of semaphorin or plexin knockout mice and discusses the association with pathogenesis and therapy of atherosclerosis, agenesis of the corpus callosum, and neuropsychiatric diseases. The deletion of semaphorin 4D in atherosclerosis-prone Apolipoprotein E-deficient mice mitigated atherosclerotic lesions, indicating its crucial involvement in the progression of atherosclerosis. Semaphorin 4D is also implicated in apoptosis induced by the estrogen-dependent generation of soluble semaphorin 4D and the active form of plexin-B1 in the postnatal vaginal opening in mice. Plexin-A1 knockout BALB/cA mice exhibited the agenesis of corpus callosum. This study indicates the crucial role of plexin-A1 in the midline crossing of callosal pioneer axons projecting from the cerebral cortex during the early phase of callosal formation. Adult plexin-A1-deficient mice exhibit reduced prepulse inhibition deficit, an endophenotype of schizophrenia, in addition to excessive self-grooming. Parvalbumin-expressing interneurons in the medial prefrontal cortex are significantly decreased in plexin-A1 knockout mice. In the parvalbumin neurons, oxidative stress is significantly increased in plexin-A1 knockout mice. Accordingly, plexin-A1 deficiency may augment oxidative stress in parvalbumin neurons, thereby impairing the parvalbumin neuron network and leading to behavioral abnormalities relevant to neuropsychiatric diseases.