Phenotypic variation that cannot be explained by genetic or environmental heterogeneity has intrigued geneticists for decades. The molecular basis of this phenomenon, however, is largely a mystery. Axin-fused (Axin Fu ), first identified in 1937, is a classic example of a mammalian allele displaying extremely variable expression states. Here we demonstrate that the presence or absence of its characteristic phenotype, a kinked tail, correlates with differential DNA methylation at a retrotransposon within Axin Fu and identify mutant transcripts arising adjacent to the retrotransposon LTR that are likely to be causative of the phenotype. Furthermore, the epigenetic state at Axin Fu can be inherited transgenerationally after both maternal and paternal transmission. This is in contrast to epigenetic inheritance at the murine agouti-viable yellow (A vy ) allele, which occurs through the female only. Unlike the egg, the sperm contributes very little (if any) cytoplasm to the zygote, and therefore paternal inheritance at Axin Fu argues against the possibility that the effects are due to cytoplasmic or metabolic influences. Consistent with the idea of transgenerational inheritance of epigenetic marks, we find that the methylation state of Axin Fu in mature sperm reflects the methylation state of the allele in the somatic tissue of the animal, suggesting that it does not undergo epigenetic reprogramming during gametogenesis. Finally, we show that epigenetic inheritance is influenced by strain background. These findings enable us to propose a model for transgenerational epigenetic inheritance in mammals.I t is generally assumed that a phenotype is determined by the interaction of a specific genotype and a specific environment, but there are a number of examples where variable expressivity and incomplete penetrance cannot be explained by genetic or environmental heterogeneity. One of the earliest documented examples is the axin-fused (Axin Fu ) allele, first identified in 1937 (1). Axin regulates embryonic axis formation in vertebrates by inhibiting the Wnt signaling pathway (2). Axin Fu is a dominant gain-of-function allele that has a 5.1-kb intracisternal-A particle (IAP) retrotransposon (subtype I⌬1) inserted in an antisense orientation (relative to the axin locus) in intron 6 (3). The characteristic Axin Fu phenotype is kinks in the tail (Fig. 1A) caused by axial duplications during embryogenesis (1, 2). The phenotype is variably expressed among Axin Fu individuals, and in some mice the tails appear completely normal; i.e., the mutant phenotype is silent.The variable expressivity of Axin Fu is reminiscent of that observed for the A iapy , A hvy , and A vy alleles of the agouti locus, all of which contain IAP (subtype I⌬1) insertions upstream of the agouti gene (4-6). The coats of isogenic mice carrying these alleles vary from wild-type agouti to completely yellow, with a spectrum of intermediate mottled coats (4-7). The variable expressivity correlates with differential DNA methylation at a cryptic promoter within the l...

Understanding the mechanisms whereby information encoded within patterns of action potentials is deciphered by neurons is central to cognitive psychology. The multiprotein complexes formed by NMDA receptors linked to synaptic membrane-associated guanylate kinase (MAGUK) proteins including synapse-associated protein 102 (SAP102) and other associated proteins are instrumental in these processes. Although humans with mutations in SAP102 show mental retardation, the physiological and biochemical mechanisms involved are unknown. Using SAP102 knock-out mice, we found specific impairments in synaptic plasticity induced by selective frequencies of stimulation that also required extracellular signal-regulated kinase signaling. This was paralleled by inflexibility and impairment in spatial learning. Improvement in spatial learning performance occurred with extra training despite continued use of a suboptimal search strategy, and, in a separate nonspatial task, the mutants again deployed a different strategy. Double-mutant analysis of postsynaptic density-95 and SAP102 mutants indicate overlapping and specific functions of the two MAGUKs. These in vivo data support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways. This provides a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.

Beyond finding individual genes that are involved in medical disorders, an important challenge is the integration of sets of disease genes with the complexities of basic biological processes. We examine this issue by focusing on neuronal multiprotein complexes and their components encoded on the human X chromosome. Multiprotein signaling complexes in the postsynaptic terminal of central nervous system synapses are essential for the induction of neuronal plasticity and cognitive processes in animals. The prototype complex is the N-methyl-D-aspartate receptor complex/membrane-associated guanylate kinase-associated signaling complex (NRC/MASC) comprising 185 proteins and embedded within the postsynaptic density (PSD), which is a set of complexes totaling approximately 1,100 proteins. It is striking that 86% (6 of 7) of X-linked NRC/MASC genes and 49% (19 of 39) of X-chromosomal PSD genes are already known to be involved in human psychiatric disorders. Moreover, of the 69 known proteins mutated in X-linked mental retardation, 19 (28%) encode postsynaptic proteins. The high incidence of involvement in cognitive disorders is also found in mouse mutants and indicates that the complexes are functioning as integrated entities or molecular machines and that disruption of different components impairs their overall role in cognitive processes. We also noticed that NRC/MASC genes appear to be more strongly associated with mental retardation and autism spectrum disorders. We propose that systematic studies of PSD and NRC/MASC genes in mice and humans will give a high yield of novel genes important for human disease and new mechanistic insights into higher cognitive functions.

Vestibular information modulates hippocampal activity for spatial processing and place cell firing. However, evidence of a purely vestibular stimulus modulating hippocampal activity is confounded as most studies use stimuli containing somatosensory and visual components. In the present study, high-frequency electrical stimulation of specific vestibular sensory regions of the right labyrinth in anaesthetized guinea pigs induced an evoked field potential in the hippocampal formation bilaterally with a latency of about 40 ms following stimulation onset. Field potentials localized in the hippocampal formation occurred with stimulus current parameters that were too small to produce eye movements. This provides direct electrophysiological evidence of vestibular input to the hippocampus.