The oculomotor periphery: the clinician''s focus is no longer a basic science stepchild

The study of the oculomotor periphery, the extraocular muscles and their orbital attachments, is undergoing a rapid expansion. This is an important progression for both basic and clinical communities as, for too long, the ophthalmologist has worked primarily in the periphery and the basic researcher has been occupied with study of the central components of the oculomotor system. From recent studies, it is clear that the morphology, cell and molecular biology, and genetics of the eye muscles and their corresponding motoneuron pools, and muscle attachments within the orbit are more complex than has heretofore been appreciated.     

Zebrafish: tools for investigating cellular differentiation

Two recent large-scale genetic screens in zebrafish have identified many mutations that affect differentiation in a variety of organ systems, particularly the notochord, the neural crest and the blood. The combination of these newly identified mutations and well established embryological methods makes zebrafish uniquely suited among vertebrate experimental systems to simultaneously address the roles of specific genes and specific cell—cell interactions during differentiation.     

Peptidergic neurohormonal control systems in invertebrates

The concerted activity of many neuropeptides has been implicated in the neurohormonal control of specific behaviors and various physiological functions in some invertebrate model systems. What are the functional consequences of this neuropeptide multiplicity? The distinct actions of closely related neuropeptides have been detected in molluscs and insects; however, recent work provides examples of systems in which some of the multiple isoforms may be functionally redundant. Groups of functionally distinct neuropeptides encoded by the same gene can be expressed in different neurons by alternative gene splicing or cell-specific post-translational processing; therefore, as shown recently, they can be targeted for release as ‘cocktails’ to act on specific sets of muscles or neurons. One prominent role of neuropeptides is to modulate the activity of rhythm-generating circuits, as exemplified by recent research on mollusc neural networks, the crab stromatogastric ganglion, and fly circadian pacemakers.     

Biorobotic approaches to the study of motor systems

Biorobotics is a promising new area of research at the interface between biology and robotics. Robots can either be used as physical models of biological systems or be directly inspired by biological studies. A great deal of progress has recently been made in biorobotic studies of locomotion, orientation, and vertebrate arm control.     

Dorsal-ventral signaling in limb development

In both Drosophila wings and vertebrate limbs, signaling between dorsal and ventral cells establishes an organizer that promotes limb formation. Significant progress has been made recently towards characterizing the signaling interactions that occur at the dorsal—ventral limb border. Studies of chicks have indicated that, as in Drosophila, this signaling process requires the participation of Fringe. Studies of Drosophila have indicated that Fringe functions by inhibiting the ability of Notch to be activated by one ligand, Serrate, while potentiating the ability of Notch to be activated by another ligand, Delta. Recent studies of both Drosophila and vertebrates have also shed new light on the signaling activity of the dorsal—ventral boundary limb organizer, and have highlighted how this organizer is maintained by feedback mechanisms with neighboring cells.     

Gen(om)e duplications in the evolution of early vertebrates

Phylogenetic analyses and sequence surveys of developmental regulator gene families indicate that two large-scale gene duplications, most likely genome duplications, occurred in ancestors of vertebrates. Relaxed constraints allowed duplicated and thus redundant genes to diverge in a two stage mechanism. Neutral changes dominated at first but then positively selected regulatory changes evolved the novel and increasingly complex vertebrate developmental program.     

Evolution of the diverse antifreeze proteins

Different types of ice-growth-inhibiting antifreeze proteins, first recognized in fish, have now been isolated from insects and plants, and the list continues to expand. Their structures are amazingly diverse; how they attain the same function are subjects of intense research. Evolutionary precursors of several members have been identified — divergent proteins of apparently unrelated function. The hybridization of information from structural and molecular evolution studies of these molecules provides a forum in which issues of selection, gene genealogy, adaptive evolution, and invention of a novel function can be coherently addressed.     

The origin of interspersed repeats in the human genome

Over a third of the human genome consists of interspersed repetitive sequences which are primarily degenerate copies of transposable elements. In the past year, the identities of many of these transposable elements were revealed. The emerging concept is that only three mechanisms of amplification are responsible for the vast majority of interspersed repeats and that with each autonomous element a number of dependent non-autonomous sequences have co-amplified.     

Plasticity and stem cells in the vertebrate nervous system

How and when do vertebrate neural precursor cells choose their fates? While some studies suggest a series of commitments on the road to fate choice, many recent experiments indicate that precursor fate choices can often be changed. Additionally, the identification of common gene control mechanisms in precursors suggest that these cells share fundamental properties throughout development.     

Biodiversity, genomes, and DNA sequence databases

There are ∼1.4 million organisms on this planet that have been described morphologically but there is no comparable coverage of biodiversity at the molecular level. Little more than 1% of the known species have been subject to any molecular scrutiny and eukaryotic genome projects have focused on a group of closely related model organisms. The past year, however, has seen an ∼80% increase in the number of species represented in sequence databases and the completion of the sequencing of three prokaryotic genomes. Large-scale sequencing projects seem set to begin coverage of a wider range of the eukaryotic diversity, including green plants, microsporidians and diplomonads.     

Solid-phase oligosaccharide synthesis and related technologies

Research efforts directed at the development of methodologies effective for solid-phase synthesis of oligosaccharides have resulted in a number of impressive achievements. In addition, closely related technologies, such as soluble polymer-supported synthesis and fluorous synthesis of the same class of molecules, have proved to be quite promising.     

Chemical approaches toward understanding base excision DNA repair

Despite the importance of DNA repair in protecting the genome, the molecular basis for damage recognition and repair remains poorly understood. In the base excision repair pathway (BER), DNA glycosylases recognize and excise damaged bases from DNA. This review focuses on the recent development of chemical approaches that have been applied to the study of BER enzymes. Several distinctive classes of noncleavable substrate analogs that form stable complexes with DNA glycosylases have recently been designed and synthesized. These analogs have been used for biochemical and structural analyses of protein—DNA complexes involving DNA glycosylases, and for the isolation of a novel DNA glycosylase. An approach to trap covalently a DNA glycosylase-intermediate complex has also been used to elucidate the mechanism of DNA glycosylases.     

Lipid polymorphism and biomembrane function

In recent years, several major developments have taken place in the biology, physical chemistry and technology of polymorphism of membrane lipids. These include the identification of polymorphic regulation of membrane lipid composition in Escherichia coli, the importance of nonbilayer lipids for protein functioning, the special packing properties of bilayers containing these lipids, and the crystalization of a membrane protein out of three dimensional bilayer networks (lipid cubic phases). These exciting developments bring us closer to understanding the paradox of the lipid bilayer structure of biomembranes and the molecular basis of membrane protein structure and function.     

Reproductive isolation in Drosophila: how close are we to untangling the genetics of speciation?

Our understanding of the genetic basis of reproductive isolation in Drosophila has progressed rapidly over the past decade. Details of the genetic structure of hybrid sterility have been revealed and a general consensus has been reached concerning the genetic bases of Haldane's rule. Genetic analyses now reach beyond hybrid sterility and inviability, allowing us to make important comparisons across different traits involved in reproductive isolation. Expansion of genetic studies to include rescue of hybrid incompatibilities has opened the door for more detailed molecular and developmental analyses of reproductive isolation than has ever before been possible.     

Metazoan phylogenies: falling into place or falling to pieces? A palaeontological perspective

Metazoan phylogeny is in a state of ferment, stirred by the addition of new molecular trees as well as controversial interpretations of molecular ‘clocks’. Concerning the latter topic, the clocks recurrently point to divergence times substantially older than the known fossil record. Some attempt reconciliation by appealing to a conveniently cryptic interval prior to the first fossils. This effectively reduces the fossil record to an erratic search-light giving only glimpses into the true evolutionary history. Other options, however, remain open. Molecular clocks may themselves run erratically and what happens in molecular history may not coincide with the emergence of body plans.     

Learning in the oculomotor system: from molecules to behavior

A combination of system-level and cellular—molecular approaches is moving studies of oculomotor learning rapidly toward the goal of linking synaptic plasticity at specific sites in oculomotor circuits with changes in the signal-processing functions of those circuits, and, ultimately, with changes in eye movement behavior. Recent studies of saccadic adaptation illustrate how careful behavioral analysis can provide constraints on the neural loci of plasticity. Studies of vestibulo-ocular adaptation are beginning to examine the molecular pathways contributing to this form of cerebellum-dependent learning.