Direct development is the assumption of the adult morphology without progression through an intervening, morphologically distinct, free-living larval phase. We discuss the ecological factors contributing to the evolution of this derived life-history strategy in frogs, and the developmental modifications that facilitate such an unusual mode of embryogenesis. Studies on the Puerto Rican tree frog, Eleutherodactylus coqui, have identified several such modifications, including developmental adaptations for dealing with increased egg size, and loss of tadpole structures. Surprisingly, this direct developer still undergoes a thyroid hormone-dependent metamorphosis, which occurs before hatching. We suggest how the ancestral biphasic developmental pattern may have been rearranged during the evolution of direct development.

Tolerance to otherwise lethal cerebral ischemia in vivo or to oxygen-glucose deprivation (OGD) in vitro can be induced by prior transient exposure to N-methyl-D-aspartic acid (NMDA): preconditioning in this manner activates extrasynaptic and synaptic NMDA receptors and can require bringing neurons to the "brink of death." We considered if this stressful requirement could be minimized by the stimulation of primarily synaptic NMDA receptors. Subjecting cultured cortical neurons to prolonged elevations in electrical activity induced tolerance to OGD. Specifically, exposing cultures to a K ؉ -channel blocker,

Brain-derived neurotrophic factor (BDNF) 1 is a member of neurotrophin family, structurally related to nerve growth factor, neurotrophin-3, and neurotrophin-4/5. Its biological activity is mediated by tyrosine kinase receptor B (TrkB) and its downstream signaling (1). The gene is highly expressed and widely distributed in the central nervous system, and it plays a significant role in the maintenance of function and survival of neurons (for review, see Ref.2). Evidence accumulated in recent years suggests that BDNF is also involved in the modulation of synaptic activity in the adult brain, producing long lasting changes in synaptic structure and function (for reviews, see Refs. 3-5).There is a growing interest in BDNF as a potential therapeutic agent for neurodegenerative diseases, because its deficiency was found in brains of both Alzheimer's and Parkinson's patients (6 -10). Indeed, BDNF treatment has been shown not only to potentiate synaptic transmission in vivo (11, 12) but also to increase neuronal survival and augment some behavioral changes in animal models (13,14). However, more recent data indicate that BDNF can also induce behavioral sensitization by causing an overexpression of dopamine D3 receptors and could, actually, contribute to the amplification of pathophysiologies associated with conditions such as epilepsy, drug addiction, schizophrenia, and Parkinson's disease (15, 16). Clearly, further work is required to resolve some of these potential side-effects. In contrast to a large body of work on the temporal and spatial patterns of BDNF expression in neurodevelopment and neurodegeneration, relatively little is known about the transcriptional regulation of the human BDNF gene. This is partially due to the fact that the genomic structure of the human gene has not yet been fully elucidated. The gene was first localized to chromosome11p13 and predicted to consist of multiple exons (17), but the existence of multiple transcripts, derived from different exons, was demonstrated only recently by Aoyama et al. (18) in human neuroblastoma cells. A more detailed transcript mapping of an 810-kb region of chromosome 11p13-14 further defined its genomic localization, although no additional information on the actual structure of the gene itself was presented (19).The existence of multiple human BDNF transcripts (18) is consistent with a genomic structure similar to that of the rat gene, which consists of four short 5Ј exons, each controlled by a distinct promoter, and one 3Ј exon encoding the mature BDNF protein (20,21). In the rat, the four promoters direct expression of the BDNF gene in a tissue-specific manner, i.e. promoters I and II are active preferentially in neurons, whereas promoters III and IV are active both in neurons and in a limited number of non-neuronal tissues such as lung and heart (20, 21). Thus far, only a limited characterization of a 3.2-kb genomic fragment of the human gene containing some structural elements of a promoter was reported (22).Recently, two transcription factors, CREB and ...

Eleutherodactylus coqui develops directly from a large 3.5-mm egg to a froglet, without an intervening tadpole stage. We have examined the development of the body wall, a structure whose behavior has been altered in this derived development. In an event that is unusual for amphibian embryos, the yolk mass is secondarily surrounded by the body wall, which originates near the embryo's trunk. The epidermis of the body wall is marked by melanophores, and the rectus abdominis, which will form the ventral musculature, is near its leading edge. As the body wall expands, the epidermis, melanophores, and rectus abdominis all move from the dorsal side to close over the yolk at the ventral midline. The original ectoderm over the yolk undergoes apoptosis, as it is replaced by body wall epidermis. Intact muscles are not required for ventral closure of the body wall, despite their normal presence near the advancing edge. Comparative examination of embryos of Xenopus laevis and Rana pipiens suggests that ventral closure does not occur in species with tadpoles. The expansion of dorsal tissues over the yolk, as illustrated by E. coqui, may have been important in the origin of amniote embryos.

The direct developing frog Eleutherodactylus coqui exhibits radical changes in its embryogenesis. A frog-like head forms directly with no appearance of a cement gland or several jaw cartilages characteristic of tadpoles, and limbs appear early in development. The numerous differences in the embryogenesis of E. coqui provide an opportunity to examine developmental causes for the evolutionary shift from biphasic to direct development. We have cloned DNA fragments corresponding to four E. coqui genes related to the Drosophila distal-less gene Dll. While the expression patterns of the distal-less genes are generally conserved, there are some spatiotemporal differences when embryos of E. coqui are compared to those of Xenopus laevis. The changes in gene expression are correlated with the embryonic changes in head structures including craniofacial cartilages and in particular, the cement gland. We have then examined inductive interactions involved in cement gland formation by interspecific transplants and recombinants. E. coqui embryos can generate signaling that culminates in cement gland formation, but E. coqui ectoderm appears to be incapable of a cement gland response. These results show here that inductive interactions in the anterior region of the E. coqui embryo have been modified during the evolution of direct development, and that changes in the competence of the E. coqui ectoderm may be responsible for the loss of certain tadpole-specific structures, such as cement gland.