Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene

The molecular mechanisms underlying the evolution of complex behaviour are poorly understood. The mammalian genus Microtus provides an excellent model for investigating the evolution of social behaviour. Prairie voles (Microtus ochrogaster) exhibit a monogamous social structure in nature, whereas closely related meadow voles (Microtus pennsylvanicus) are solitary and polygamous. In male prairie voles, both vasopressin and dopamine act in the ventral forebrain to regulate selective affiliation between adult mates, known as pair bond formation, as assessed by partner preference in the laboratory. The vasopressin V1a receptor (V1aR) is expressed at higher levels in the ventral forebrain of monogamous than in promiscuous vole species, whereas dopamine receptor distribution is relatively conserved between species. Here we substantially increase partner preference formation in the socially promiscuous meadow vole by using viral vector V1aR gene transfer into the ventral forebrain. We show that a change in the expression of a single gene in the larger context of pre-existing genetic and neural circuits can profoundly alter social behaviour, providing a potential molecular mechanism for the rapid evolution of complex social behaviour.     

Lanthanide-binding peptides and the enzymes that Might Have Been

The trivalent lanthanide ions are chemically similar to Ca(II) ions, making them useful Ca analogs for a multitude of applications. In addition, Ln(III) ions are efficient catalysts of hydrolysis due to their much stronger Lewis acidity relative to Ca(II) ions. Ln-binding peptides thus offer both the opportunity to study known Ca sites as well as to explore new biological functions with an entire family of spectroscopically rich and reactive ions. This review discusses Ln-binding peptides in three roles: (i) as models of Ca-protein structure and function, (ii) as spectroscopic tags for protein expression and characterization and (iii) as designed artificial endonucleases. The creation of hydrolytically active Ln peptides that can fold, bind, cleave and discriminate among substrates shows that the design of Ln enzymes can be accomplished, and they will serve as versatile biochemical tools to investigate protein folding, structure and nuclease function.Received 10 April 2004; received after revision 17 May 2004; accepted 28 May 2004     

Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT

Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentrations, itching, and fat malabsorption. We show here that FHC in Amish individuals is associated with mutations in tight junction protein 2 (encoded by TJP2, also known as ZO-2) and bile acid Coenzyme A: amino acid N-acyltransferase (encoded by BAAT). The mutation of TJP2, which occurs in the first PDZ domain, reduces domain stability and ligand binding in vitro. We noted a morphological change in hepatic tight junctions. The mutation of BAAT, a bile acid-conjugating enzyme, abrogates enzyme activity; serum of individuals homozygous with respect to this mutation contains only unconjugated bile acids. Mutations in both TJP2 and BAAT may disrupt bile acid transport and circulation. Inheritance seems to be oligogenic, with genotype at BAAT modifying penetrance in individuals homozygous with respect to the mutation in TJP2.     

Glia maturation factor influences recovery from injury in neonatal rat brains

Newborn rats were injured with a puncture wound in one cerebral hemisphere. Experimental animals were treated with three i.p. injections of Glia Maturation Factor (GMF) at daily intervals starting from the time of injury, whereas control littermates were treated with equivalent amounts of bovine serum albumin. At 25 days old the size of the cerebral cortex at the plane of injury was measured on representative brain sections. In control rats the injured side was 18% smaller than the normal side whereas in GMF-treated animals the difference was only 1%. The results suggest a possible regulatory role of GMF in promoting tissue recovery from brain damage.     

Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system

Mouse embryos deficient in Gata3 die by 11 days post coitum (d.p.c.) from pathology of undetermined origin. We recently showed that Gata3-directed lacZ expression of a 625-kb Gata3 YAC transgene in mice mimics endogenous Gata3 expression, except in thymus and the sympathoadrenal system. As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants. We find here that null mutation of Gata3 leads to reduced accumulation of Th (encoding tyrosine hydroxylase, Th) and Dbh (dopamine beta-hydroxylase, Dbh) mRNA, whereas several other SNS genes are unaffected. We show that Th and Dbh deficiencies lead to reduced noradrenaline in the SNS, and that noradrenaline deficiency is a proximal cause of death in mutants by feeding catechol intermediates to pregnant dams, thereby partially averting Gata3 mutation-induced lethality. These older, pharmacologically rescued mutants revealed abnormalities that previously could not be detected in untreated mutants. These late embryonic defects include renal hypoplasia and developmental defects in structures derived from cephalic neural crest cells. Thus we have shown that Gata3 has a role in the differentiation of multiple cell lineages during embryogenesis.     

Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans

Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.