Selective effects of protein 4.1N deficiency on neuroendocrine and reproductive systems

Protein 4.1N, a member of the protein 4.1 family, is highly expressed in the brain. But its function remains to be fully defined. Using 4.1N(−/−) mice, we explored the function of 4.1N in vivo. We show that 4.1N(−/−) mice were born at a significantly reduced Mendelian ratio and exhibited high mortality between 3 to 5 weeks of age. Live 4.1N(−/−) mice were smaller than 4.1N(+/+) mice. Notably, while there were no significant differences in organ/body weight ratio for most of the organs, the testis/body and ovary/body ratio were dramatically decreased in 4.1N(−/−) mice, demonstrating selective effects of 4.1N deficiency on the development of the reproductive systems. Histopathology of the reproductive organs showed atrophy of both testis and ovary. Specifically, in the testis there is a lack of spermatogenesis, lack of leydig cells and lack of mature sperm. Similarly, in the ovary there is a lack of follicular development and lack of corpora lutea formation, as well as lack of secretory changes in the endometrium. Examination of pituitary glands revealed that the secretory granules were significantly decreased in pituitary glands of 4.1N(−/−) compared to 4.1N(+/+). Moreover, while GnRH was expressed in both neuronal cell body and axons in the hypothalamus of 4.1N(+/+) mice, it was only expressed in the cell body but not the axons of 4.1N(-/-) mice. Our findings uncover a novel role for 4.1N in the axis of hypothalamus-pituitary gland-reproductive system.