Biology of the brain and muscle Arnt-like protein-1(BMAL1): Roles in reproductive biology

Brain and muscle Arnt-like protein (BMAL1) is a basic-helix-loop-helix (bHLH) transcription factor and member of the Per-ARNT-Sim (PAS) super family. Bmal1 is an essential component of the circadian clock. Circadian rhythms play important roles in areas as diverse as cancer biology, reproductive biology, metabolism, energy balance and aging. Mice with global deletion of Bmal1 display profound defects such as infertility, disrupted endocrinology, diabetes, early aging and arthropathy. In an effort to determine the roles of peripheral clocks and central clocks in reproductive biology, we used Cre/loxP recombination technology to genetically delete Bmal1 specifically in various cell types with implicated roles in reproduction. In the first chapter of this thesis, we review what is currently known about the links among circadian rhythms, endocrinology and reproductive biology. In chapter two we show that the disruption of Bmal1 in peripheral steroidogenic cells (Bmal1fx/fxCresf-1) results in female infertility due to implantation failure. Bmal1fx/fx Cresf-1 females have lower progesterone levels than control females, and progesterone supplementation was able to rescue implantation. Transplantation of wild type ovaries into Bmal1 fx/fxCresf-1 females results in 100% fertility, suggesting that ovarian Bmal1 is the primary peripheral clock governing implantation and fertility in female mice. In chapter three, we compare the relative roles of Bmal1 in central nervous system (Bmal1fx/fxCrenestin) and various peripheral cell types including the reproductive hormone axis (Bmal1 fx/fxCresf-1), leydig cells or granulosa cells (Bmal1fx/fxCreAmhr2), pituitary cells (somatotrophs, lactotrophs) (Bmal1fx/fxCre rGhrhr) in male and female fertility. Only Bmal1 fx/fxCrenestin males display defects in fertility (50% infertile). Bmal1fx/fxCresf-1, Bmal1fx/fxCreAmhr2, Bmal1 fx/fxCrerGhrhr males are fertile, suggesting the importance of clocks in central nervous system for male fertility. Bmal1fx/fxCrenestin, Bmal1 fx/fxCreAmhr2, Bmal1fx/fxCre rGhrhr females are fertile, consistent with the importance of ovarian Bmal1 for female fertility. In chapter 4 we present future approaches to further elucidate the major themes of this thesis.