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.

蛋白4.1N是蛋白4.1家族的成员，在大脑中高度表达，但其功能仍有待完全明确。我们利用4.1N基因敲除小鼠在体内探究了4.1N的功能。我们发现4.1N基因敲除小鼠以显著降低的孟德尔比例出生，并且在3至5周龄之间呈现高死亡率。存活的4.1N基因敲除小鼠比4.1N野生型小鼠体型更小。值得注意的是，虽然大多数器官的器官/体重比没有显著差异，但4.1N基因敲除小鼠的睾丸/体重和卵巢/体重比显著降低，这表明4.1N缺失对生殖系统发育具有选择性影响。生殖器官的组织病理学显示睾丸和卵巢均萎缩。具体而言，在睾丸中，精子发生缺失，睾丸间质细胞缺失，成熟精子缺失。同样，在卵巢中，卵泡发育缺失，黄体形成缺失，子宫内膜也没有分泌性变化。对垂体的检查显示，与4.1N野生型相比，4.1N基因敲除小鼠垂体中的分泌颗粒显著减少。此外，促性腺激素释放激素（GnRH）在4.1N野生型小鼠下丘脑的神经元胞体和轴突中均有表达，但在4.1N基因敲除小鼠中仅在胞体表达，而不在轴突表达。我们的研究结果揭示了4.1N在下丘脑 - 垂体 - 生殖系统轴中的一种新作用。