Department of Biological Sciences

Professor

Kazuaki YOSHIKAWA

yoshikaw@protein.osaka-u.ac.jp

Assistant Professor

Koichi HASEGAWA

hasegawa@protein.osaka-u.ac.jp

Assistant Professor

Kazushiro FUJIWARA

fuji-k@protein.osaka-u.ac.jp

Molecular mechanisms of neuronal terminal differentiation

Necdin, which was discovered by our group in 1991, is expressed predominantly in postmitotic neurons. This protein is capable of suppressing proliferation and apoptosis of neurons to stabilize their terminal differentiation. The human necdin gene NDN is expressed only from the paternal allele through genomic imprinting, and its deficiency is implicated in the pathogenesis of the neurodevelopmental disorder Prader-Willi syndrome. Necdin shows a moderate homology to the MAGE (melanoma antigen) family proteins, which are speculated to be involved in proliferation, differentiation, and death of stem cells. We are studying the expression and function of necdin and its related MAGE family proteins in neuronal terminal differentiation by gene manipulations of model animals and cells.

Molecular mechanisms of neuronal death

Massive amounts of neuronal death occur in neurodegenerative diseases such as Alzheimer’s disease and during physiological development. APP is the precursor of beta-amyloid protein, which is deposited in the brain affected by Alzheimer’s disease. This protein is thought to control the survival and death of neurons during brain development. On the other hand, cell cycle regulatory proteins that regulate the proliferation of neural stem cells are reactivated in the affected brain. We are studying the link between cell cycle regulation and neuronal death.

Molecular mechanisms of brain evolution

Brain neurons count ~250,000 in fruit fly and ~100,000,000,000 in man. These neuron numbers are primarily determined during the period of neurogenesis. Fundamental mechanisms of neurogenesis are considered to be common in man and fly. We are studying molecular mechanisms of neurogenesis in model animals such as fruit fly and mouse with which large amounts of genetic information have been accumulated. These studies may provide insights into the molecular basis of brain evolution.

Intracellular translocations of necdin. In gene-transfected cells, necdin moves into the nucleus when coexpressed with the transcription factor E2F1 and into the proximity to the plasma membrane when coexpressed with the neurotrophin receptor p75 (confocal laser microscopic images).

An animal model for genomic imprinting disorder. Mice with brown eyes and hair are defective in the paternal necdin gene. They look normal but display various abnormalities in neuronal differentiation and survival. These mice are useful for studies on the pathogenesis of Prader-Willi syndrome.