Contributions of theoretical modeling to the understanding of neural map development

Theoretical/computational models have played an important role in developing our understanding of the fundamental mechanisms involved in neural map formation. I review models based on both chemospecific and activity-dependent matching of inputs to targets, with a particular focus on map development in the optic tectum and primary visual cortex.     

The evolution of chordate neural segmentation

Amphioxus is the closest relative to vertebrates but lacks key vertebrate characters, like rhombomeres, neural crest cells, and the cartilaginous endoskeleton. This reflects major differences in the developmental patterning of neural and mesodermal structures between basal chordates and vertebrates. Here, we analyse the expression pattern of an amphioxus FoxB ortholog and an amphioxus single-minded ortholog to gain insight into the evolution of vertebrate neural segmentation. AmphiFoxB expression shows cryptic segmentation of the cerebral vesicle and hindbrain, suggesting that neuromeric segmentation of the chordate neural tube arose before the origin of the vertebrates. In the forebrain, AmphiFoxB expression combined with AmphiSim and other amphioxus gene expression patterns shows that the cerebral vesicle is divided into several distinct domains: we propose homology between these domains and the subdivided diencephalon and midbrain of vertebrates. In the Hox-expressing region of the amphioxus neural tube that is homologous to the vertebrate hindbrain, AmphiFoxB shows the presence of repeated blocks of cells along the anterior-posterior axis, each aligned with a somite. This and other data lead us to propose a model for the evolution of vertebrate rhombomeric segmentation, in which rhombomere evolution involved the transfer of mechanisms regulating neural segmentation from vertical induction by underlying segmented mesoderm to horizontal induction by graded retinoic acid signalling. A consequence of this would have been that segmentation of vertebrate head mesoderm would no longer have been required, paving the way for the evolution of the unsegmented head mesoderm seen in living vertebrates.     

Darwin's contributions to our understanding of emotional expressions

Darwin charted the field of emotional expressions with five major contributions. Possible explanations of why he was able to make such important and lasting contributions are proposed. A few of the important questions that he did not consider are described. Two of those questions have been answered at least in part; one remains a major gap in our understanding of emotion.     

Early contributions of molecular phylogenetics to understanding the evolution of Rotifera

The past decade has seen the application of DNA sequence data to phylogenetic investigations of Rotifera, both expanding and challenging our understanding of the evolution of the phylum. Evidence that Acanthocephala, long regarded as a separate but closely related phylum, is a highly derived class of Rotifera demonstrates the potential of molecular analyses to suggest relationships not obvious from morphological analysis. Phylogenies based on the sequence of the gene for the small ribosomal RNA suggest that rotifers and acanthocephalans are associated with Platyhelminthes and Gastrotricha, perhaps in a clade with Gnathostomula and Cycliophora; at present, this group lacks a clear morphological synapomorphy. A more complete resolution of the molecular phylogeny of Rotifera will require surveying multiple genes and several species from each clade under investigation.     

Symmetry breaking and convergent extension in early chordate development

The initiation of axis, polarity, cell differentiation, and gastrulation in the very early chordate development is due to the breaking of radial symmetry. It is believed that this occurs by an external signal. We suggest instead spontaneous symmetry breaking through the agency of the Turing-Child field. Increased size or decreased diffusivity, both brought about by mitotic activity, cause the spontaneous loss of stability of the homogeneous state and the evolution of the metabolic pattern during development. The polar metabolic pattern is the cause of polar gene expression, polar morphogenesis (gastrulation), and polar mitotic activity. The Turing-Child theory explains not only the spontaneous formation of the invagination in gastrulation but also the coherent cell movement observed in convergence and extension during gastrulation and neurulation. The theory is demonstrated with respect to experimental observations on the early development of fish, amphibian, and the chick. The theory can explain a multitude of experimental details. For example, it explains the splayed polar progression of reduction in the fish blastoderm. Reduction starts on that side of the blastoderm margin, which will initiate invagination several hours later. It progresses toward the blastoderm center and somewhat laterally from this future "dorsal lip". This is precisely as predicted by a Turing-Child system in a circle. And for a fish like zebrafish with a blastoderm that is slightly oval, reduction is observed to progress along the long axis of the ellipse, which is what Turing-Child theory predicts. In general the shape and the chemical nature of the experimental patterns are the same as predicted by the Turing couple (cAMP, ATP). Embryological polarity and convergent extension are based on polar eigenfunction and saddle-shaped eigenfunction, respectively.     

Amphioxus postembryonic development reveals the homology of chordate metamorphosis

Most studies in evolution are centered on how homologous genes, structures, and/or processes appeared and diverged. Although historical homology is well defined as a concept, in practice its establishment can be problematic, especially for some morphological traits or developmental processes. Metamorphosis in chordates is such an enigmatic character. Defined as a spectacular postembryonic larva-to-adult transition, it shows a wide morphological diversity between the different chordate lineages, suggesting that it might have appeared several times independently. In vertebrates, metamorphosis is triggered by binding of the thyroid hormones (THs) T(4) and T(3) to thyroid-hormone receptors (TRs). Here we show that a TH derivative, triiodothyroacetic acid (TRIAC), induces metamorphosis in the cephalochordate amphioxus. The amphioxus TR (amphiTR) mediates spontaneous and TRIAC-induced metamorphosis because it strongly binds to TRIAC, and a specific TR antagonist, NH3, inhibits both spontaneous and TRIAC-induced metamorphosis. Moreover, as in amphibians, amphiTR expression levels increase around metamorphosis and are enhanced by THs. Therefore, TH-regulated metamorphosis, mediated by TR, is an ancestral feature of all chordates. This conservation of a regulatory network supports the homology of metamorphosis in the chordate lineage.     

Recent contributions from solid-state NMR to the understanding of membrane protein structure and function

The plasma membrane functions as a semi-permeable barrier, defining the interior (or cytoplasm) of an individual cell. This highly dynamic and complex macromolecular assembly comprises predominantly lipids and proteins held together by entropic forces and provide the interface through which a cell interacts with its immediate environment. The extended sheet-like bilayer structure formed by the phospholipids is a highly adaptable platform whose structure and composition may be tuned to provide specialised functionality. Although a number of biophysical techniques including X-ray crystallography have been used to determine membrane protein structures, these methods are unable to replicate and accommodate the complexity and diversity of natural membranes. Solid state NMR (ssNMR) is a versatile method for structural biology and can be used to provide new insights into the structures of membrane components and their mutual interactions. The extensive variety of sample forms amenable for study by ssNMR, allows data to be collected from proteins in conditions that more faithfully resemble those of native environment, and therefore is much closer to a functional state.     

Differential contributions of Ng-CAM and N-CAM to cell adhesion in different neural regions

Individual neurons can express both the neural cell adhesion molecule (N-CAM) and the neuron-glia cell adhesion molecule (Ng-CAM) at their cell surfaces. To determine how the functions of the two molecules may be differentially controlled, we have used specific antibodies to each cell adhesion molecule (CAM) to perturb its function, first in brain membrane vesicle aggregation and then in tissue culture assays testing the fasciculation of neurite outgrowths from cultured dorsal root ganglia, the migration of granule cells in cerebellar explants, and the formation of histological layers in the developing retina. Our strategy was initially to delineate further the binding mechanisms for each CAM. Antibodies to Ng-CAM and N-CAM each inhibited brain membrane vesicle aggregation but the binding mechanisms of the two CAMs differed. As expected from the known homophilic binding mechanism of N-CAM, anti-N- CAM-coated vesicles did not co-aggregate with uncoated vesicles. Anti- Ng-CAM-coated vesicles readily co-aggregated with uncoated vesicles in accord with a postulated heterophilic binding mechanism. It was also shown that N-CAM was not a ligand for Ng-CAM. In contrast to assays with brain membrane vesicles, cellular systems can reveal functional differences for each CAM reflecting its relative amount (prevalence modulation) and location (polarity modulation). Consistent with this, each of the three cellular processes examined in vitro was preferentially inhibited only by anti-N-CAM or by anti-Ng-CAM antibodies. Both neurite fasciculation and the migration of cerebellar granule cells were preferentially inhibited by anti-Ng-CAM antibodies. Anti-N-CAM antibodies inhibited the formation of histological layers in the retina. The data on perturbation by antibodies were correlated with the relative levels of expression of Ng-CAM and N-CAM in each of these different neural regions. Quantitative immunoblotting experiments indicated that the relative Ng-CAM/N-CAM ratios in comparable extracts of brain, dorsal root ganglia, and retina were respectively 0.32, 0.81, and 0.04. During culture of dorsal root ganglia in the presence of nerve growth factor, the Ng-CAM/N-CAM ratio rose to 4.95 in neurite outgrowths and 1.99 in the ganglion proper, reflecting both polarity and prevalence modulation. These results suggest that the relative ability of anti-Ng-CAM and anti-N-CAM antibodies to inhibit cell-cell interactions in different neural tissues is strongly correlated with the local Ng-CAM/N-CAM ratio.(ABSTRACT TRUNCATED AT 400 WORDS)     

Structure and function of the notochord: an essential organ for chordate development

The notochord is the defining structure of the chordates, and has essential roles in vertebrate development. It serves as a source of midline signals that pattern surrounding tissues and as a major skeletal element of the developing embryo. Genetic and embryological studies over the past decade have informed us about the development and function of the notochord. In this review, I discuss the embryonic origin, signalling roles and ultimate fate of the notochord, with an emphasis on structural aspects of notochord biology.     

Decoding the language of epigenetics during neural development is key for understanding development as well as developmental neurotoxicity

Neural development is a delicate process that can be disrupted by pollution that exerts detrimental impact on neural signaling. This commentary highlights recent discoveries in the arena of research at the interface of environmental toxicology and developmental neuroscience relating to toxicity mechanisms of bisphenol A (BPA), a ubiquitous chemical used in manufacturing of plastics and epoxy resins that is known to bind to and interfere with estrogen receptors, estrogen-receptor-related receptors and other receptors for gonadal steroids. It was recently observed that BPA disrupts the perinatal chloride shift, a key neurodevelopmental mechanism that brings down neuronal chloride from ~100 mM to ~20 mM within weeks. The chloride shift happens in all central nervous systems of vertebrates around parturition. High neuronal chloride supports neuron precursors’ migrations, low neuronal chloride is the prerequisite for inhibitory action of neurotransmitters GABA and glycine, and thus an absolute requisite for normal functioning of the mature CNS. One critical contributor to the neuronal chloride shift is the concomitant upregulation of expression of the chloride-extruding transporter molecule, KCC2. We highlight recent findings including our discovery that BPA disrupts the chloride shift in a sex-specific manner by recruiting epigenetics mechanisms. These could be relevant for childhood neuropsychiatric disorders as well as for liability to develop chronic neuropsychiatric diseases later in life.     

Estrogenic contributions to sexual differentiation in the female guinea pig: influences of diethylstilbestrol and tamoxifen on neural, behavioral, and ovarian development

We administered the synthetic estrogen, diethylstilbestrol (DES), or the antiestrogen, tamoxifen, to pregnant guinea pigs and observed the consequences for sexual differentiation of their female offspring. Hormones were administered during the period when treatment of fetuses with testosterone influences the development of sex-related traits (approximately Days 30 to 65 of gestation). Ovarian function, masculine and feminine sexual behavior, and the structure of a sexually dimorphic neural region in the preoptic area were assessed in adulthood in hormone-exposed animals and in oil-treated and untreated controls. Prenatal exposure to DES dipropionate (DESDP) caused masculinization and defeminization. DESDP-treated females mounted more than control females, both without hormonal stimulation and when given testosterone propionate (TP) as adults. The sexually dimorphic neural region was also masculinized in these females. In regard to defeminization, they showed delayed vaginal opening, impaired progesterone (P) production, an absence of corpora lutea, and impaired lordosis and mounting responses to estradiol benzoate (EB) and P. Prenatal treatment with tamoxifen produced a complicated pattern of results. Tamoxifen-exposed females evidenced less masculine-typical behavior, showing diminished mounting without hormonal stimulation and in response to TP. However, they also showed delayed vaginal opening, enhanced P production, and impaired mounting in response to EB and P. Their lordosis behavior and the volume of the sexually dimorphic neural region were unaffected. These results suggest that estrogens play a substantial role in sexual differentiation in the guinea pig. High levels of estrogen promote masculine-typical development, and unusually low levels may impair some aspects of both masculine-typical and feminine-typical development.