Nuclear receptor functions in the central nervous system : Clues from knockout mice

The nuclear receptor (NR) superfamily is the largest known family of transcription factors in eukaryotes. In the 1980’s when the size of the NR family and the scope of the functions of its members were being discovered, tissue distribution studies revealed that the mRNAs of many of these receptors were expressed in the central nervous system. The difficult task of uncovering the functions of these receptors in the brain is still ongoing. In this thesis the functions of two of the members of the NR superfamily have been studied: the estrogen receptor β (ERβ) and the liver X receptor β (LXRβ). ERβ knockout (ERβ) mice have provided evidence for a role for ERβ in neuronal survival in both the developing and in the adult brain. When proliferating cells were labeled with 5'-bromodeoxyuridine (BrdUrd) between embryonic day (E) 14.5 and E16.5 fewer BrdUrd-labeled cells could be detected in the upper cortical layers by E18.5 and postnatal day 14 in mice lacking ERβ. The migration of these neurons seems to be impaired and the processes of the cortical radial glia, which are essential for guiding the migrating neurons, were fragmented. In addition, more apoptotic cells were detected in the ventricular zone of ERβ mice at E18.5. By influencing migration and neuronal survival, ERβ has an important function during brain development. Adult ERβ mice show regional neuronal hypocellularity, especially in the cerebral cortex, and proliferation of astroglial cells in the limbic system. The neuronal deficit becomes more pronounced as ERβ mice age, indicating a neuroprotective role for ERβ. By 2 years of age there is degeneration of neuronal cell bodies throughout the brain and this is particularly evident in the cortex and the substantia nigra. During embryonic development there is a limited exposure of the brain to 17βestradiol, and this raised the question of whether ERβ is ligand-activated during this stage. We have examined the possibility that an alternative ligand for ERβ in the developing brain is 5α-androstane-3β, 17β-diol (3βAdiol). In mice, in which the pathway for degradation of 3βAdiol is inactivated (CYP7B1 knockout mice), there is an increase in the number of neurons in the brain and a profound decrease in apoptosis between E13.5-15.5. The enlargement of the brain persisted to 14 days postnatally but brain size was normalized by the time mice were 3 months old suggesting that the excess cells must have been removed in the late postnatal period. These data are supportive evidence for a role for the ERβ-3βAdiol-CYP7B1 pathway in regulation of neuronal survival in the embryonic brain. LXRβ is an oxysterol-activated nuclear receptor that plays a crucial role in the regulation of cholesterol and sterol trafficking between tissues. In LXRβ knockout mice motor co-ordination is impaired when male mice are 7 months of age. This phenomenon is associated with lipid accumulation and loss of motor neurons in the spinal cord, together with axonal atrophy and astrogliosis. Several of these features are reminiscent of the neuropathological signs of chronic motor neuron disease such as amyotrophic lateral sclerosis. We speculate that absence of LXRβ leads to pathological accumulation of sterols and lipids that may themselves be neurotoxic or may modulate intracellular pathways and thereby predispose motor neurons to degeneration. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to by their Roman