Advances in understanding of Rett syndrome and MECP2 duplication syndrome: prospects for future therapies.

The X-linked gene encoding MECP2 is involved in two severe and complex neurodevelopmental disorders. Loss of function of the MeCP2 protein underlies Rett syndrome, whereas duplications of the MECP2 locus cause MECP2 duplication syndrome. Research on the mechanisms by which MeCP2 exerts effects on gene expression in neurons, studies of animal models bearing different disease-causing mutations, and more in-depth observations of clinical presentations have clarified some issues even as they have raised further questions.

Reconceiving the hippocampal map as a topological template.

The role of the hippocampus in spatial cognition is incontrovertible yet controversial. Place cells, initially thought to be location-specifiers, turn out to respond promiscuously to a wide range of stimuli. Here we test the idea, which we have recently demonstrated in a computational model, that the hippocampal place cells may ultimately be interested in a space's topological qualities (its connectivity) more than its geometry (distances and angles); such higher-order functioning would be more consistent with other known hippocampal functions.

Safeguards for cell cooperation in mouse embryogenesis shown by genome-wide cheater screen.

Ensuring cooperation among formerly autonomous cells has been a central challenge in the evolution of multicellular organisms. One solution is monoclonality, but this option still leaves room for exploitative behavior, as it does not eliminate genetic and epigenetic variability. We therefore hypothesized that embryonic development must be protected by robust regulatory mechanisms that prevent aberrant clones from superseding wild-type cells.

It takes two: communication between homologous alleles preserves genomic stability during V(D)J recombination.

Chromosome pairing is involved in X chromosome inactivation, a classic instance of monoallelic gene expression. Antigen receptor genes are also monoallelically expressed ("allelically excluded") by B and T lymphocytes, and we asked whether pairing contributed to the regulation of V(D)J recombination at these loci. We found that homologous immunoglobulin (Ig) alleles pair up during recombination.

Recent insights into the formation of RAG-induced chromosomal translocations.

Chromosomal translocations are found in many types of tumors, where they may be either a cause or a result of malignant transformation. In lymphoid neoplasms, however, it is dear that pathogenesis is initiated by any of a number of recurrent DNA rearrangements. These particular translocations typically place an oncogene under the regulatory control of an Ig or TCR gene promoter, dysregulating cell growth, differentiation, or apoptosis.

Rag mutations reveal robust alternative end joining.

Mammalian cells repair DNA double-strand breaks (DSBs) through either homologous recombination or non-homologous end joining (NHEJ). V(D)J recombination, a cut-and-paste mechanism for generating diversity in antigen receptors, relies on NHEJ for repairing DSBs introduced by the Rag1-Rag2 protein complex. Animals lacking any of the seven known NHEJ factors are therefore immunodeficient.

Amino acid residues in Rag1 crucial for DNA hairpin formation.

The Rag proteins carry out V(D)J recombination through a process mechanistically similar to cut-and-paste transposition. Specifically, Rag complexes form DNA hairpins through direct transesterification, using a catalytic Asp-Asp-Glu (DDE) triad in Rag1. How is sufficient DNA distortion introduced to allow hairpin formation? We hypothesized that, like certain transposases, the Rag proteins might use aromatic amino acid residues to stabilize a flipped-out base.

B cell development leads off with a base hit: dU:dG mismatches in class switching and hypermutation.

The mechanisms underlying somatic hypermutation (SHM) and class switch recombination (CSR) have been the subject of much debate. Recent studies from the Neuberger and Honjo labs have lent insight into these distinct processes, and we discuss a new, comprehensive model for how AID, uracil DNA glycosylase (UNG) and the mismatch repair system function in both SHM and CSR.

V(D)J recombination: how to tame a transposase.

Since the discovery that the recombination-activating gene (RAG) proteins were capable of transposition in vitro, investigators have been trying to uncover instances of transposition in vivo and understand how this transposase has been harnessed to do useful work while being inhibited from causing deleterious chromosome rearrangements. How to preserve the capacity of the recombinase to promote a certain class of rearrangements while curtailing its ability to catalyze others is an interesting problem. In this review, we examine the progress that has been made toward understanding the regulatory mechanisms that prohibit transposition in order to formulate a model that takes into account the diverse observations that have been made over the last 15 years.

The V(D)J recombinase efficiently cleaves and transposes signal joints.

V(D)J recombination generates two types of products: coding joints, which constitute the rearranged variable regions of antigen receptor genes, and signal joints, which often form on immunologically irrelevant, excised circular molecules that are lost during cell division. It has been widely believed that signal joints simply convert reactive broken DNA ends into safe, inert products. Yet two curious in vivo observations made us question this assumption: signal ends are far more abundant than coding ends, and signal joints form only after RAG expression is downregulated.

A recombinase diversified: new functions of the RAG proteins.

The RAG proteins were long thought to serve merely as a nuclease, initiating recombination by cleaving DNA. Recent work has shown, however, that these proteins are essential for many steps in the recombination pathway, such as opening hairpins and joining broken DNA ends, and that they can also act as a transposase, targeting distorted DNA structures such as hairpins.