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David M Gardiner

Publications and source records attributed to David M Gardiner.

7 recordsLinked to original sources
PubMed2006

Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates.

Dietary and xenobiotic compounds can disrupt endocrine signaling, particularly of steroid receptors and sexual differentiation. Evidence is also mounting that implicates environmental agents in the growing epidemic of obesity. Despite a long-standing interest in such compounds, their identity has remained elusive. Here we show that the persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces the differentiation of adipocytes in vitro and increases adipose mass in vivo. TBT is a dual, nanomolar affinity ligand for both the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor gamma (PPARgamma). TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased epididymal adipose mass in adults. In the amphibian Xenopus laevis, ectopic adipocytes form in and around gonadal tissues after organotin, RXR, or PPARgamma ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPARgamma activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.

Adipogenesis↗
PubMed2005

Ontogenetic decline of regenerative ability and the stimulation of human regeneration.

Although we cannot regenerate our limbs today, it is likely that when we were embryos we could regenerate many of our tissues, including our limbs. Like other vertebrates, our impressive regenerative abilities were lost during embryogenesis, leaving us with a relatively limited ability to repair tissue damage. In contrast, adult salamanders can reactivate the embryonic regeneration response, and thus they provide the opportunity to discover the principles and mechanisms of tissue and organ regeneration. One important lesson we have learned from salamanders is that regeneration occurs in two steps. While the second step shares the mechanisms of growth control and pattern formation with limb development, the first step is unique and leads to the formation of a regeneration blastema. A second lesson is that connective tissue fibroblasts control regeneration, and that the unique regenerative ability of salamanders (the first step of regeneration) is a consequence of the ability of fibroblasts to dedifferentiate and give rise to blastema cells. Since we all developed limbs as embryos, we all possess the genetic program for making a limb (the second step of regeneration). Therefore, the challenge for inducing limb regeneration in humans is to discover how to induce fibroblast dedifferentiation.

Animals↗
PubMed2004

From biomedicine to natural history research: EST resources for ambystomatid salamanders.

BACKGROUND: Establishing genomic resources for closely related species will provide comparative insights that are crucial for understanding diversity and variability at multiple levels of biological organization. We developed ESTs for Mexican axolotl (Ambystoma mexicanum) and Eastern tiger salamander (A. tigrinum tigrinum), species with deep and diverse research histories. RESULTS: Approximately 40,000 quality cDNA sequences were isolated for these species from various tissues, including regenerating limb and tail. These sequences and an existing set of 16,030 cDNA sequences for A. mexicanum were processed to yield 35,413 and 20,599 high quality ESTs for A. mexicanum and A. t. tigrinum, respectively. Because the A. t. tigrinum ESTs were obtained primarily from a normalized library, an approximately equal number of contigs were obtained for each species, with 21,091 unique contigs identified overall. The 10,592 contigs that showed significant similarity to sequences from the human RefSeq database reflected a diverse array of molecular functions and biological processes, with many corresponding to genes expressed during spinal cord injury in rat and fin regeneration in zebrafish. To demonstrate the utility of these EST resources, we searched databases to identify probes for regeneration research, characterized intra- and interspecific nucleotide polymorphism, saturated a human - Ambystoma synteny group with marker loci, and extended PCR primer sets designed for A. mexicanum / A. t. tigrinum orthologues to a related tiger salamander species. CONCLUSIONS: Our study highlights the value of developing resources in traditional model systems where the likelihood of information transfer to multiple, closely related taxa is high, thus simultaneously enabling both laboratory and natural history research.

Ambystoma↗
PubMed2004

A stepwise model system for limb regeneration.

The amphibian limb is a model that has provided numerous insights into the principles and mechanisms of tissue and organ regeneration. While later stages of limb regeneration share mechanisms of growth control and patterning with limb development, the formation of a regeneration blastema is controlled by early events that are unique to regeneration. In this study, we present a stepwise experimental system based on induction of limb regeneration from skin wounds that will allow the identification and functional analysis of the molecules controlling this early, critical stage of regeneration. If a nerve is deviated to a skin wound on the side of a limb, an ectopic blastema is induced. If a piece of skin is grafted from the contralateral side of the limb to the wound site concomitantly with nerve deviation, the ectopic blastema continues to grow and forms an ectopic limb. Our analysis of dermal cell migration, contribution, and proliferation indicates that ectopic blastemas are equivalent to blastemas that form in response to limb amputation. Signals from nerves are required to induce formation of both ectopic and normal blastemas, and the diversity of positional information provided by blastema cells derived from opposite sides of the limb induces outgrowth and pattern formation. Hence, this novel and convenient stepwise model allows for the discovery of necessary and sufficient signals and conditions that control blastema formation, growth, and pattern formation during limb regeneration.

Ambystoma mexicanum↗
PubMed2002

Cyclopamine induces digit loss in regenerating axolotl limbs.

Axolotls, with their extensive ability to regenerate as adults, provide a useful model for studying the mechanisms of regeneration in a vertebrate, in hopes of understanding why other vertebrates cannot regenerate. Although the expression of many genes has been described in regeneration, techniques for gain and loss of function analyses have been limited. We demonstrated in a previous study that gain of function for secreted proteins was possible in the axolotl using the vaccinia virus to drive expression of the transgene. In this study, we used a pharmacological approach made possible by the existence of a naturally occurring compound that specifically blocks shh signaling, cyclopamine. The treatment of axolotls with cyclopamine during the process of limb regeneration caused a loss of digits similar to that described for the shh knockout mouse. Our results further demonstrate that shh signaling and function are conserved during limb regeneration in urodeles as in limb development in other vertebrates.

Ambystoma↗
PubMed2002

Vertebrate limb regeneration and the origin of limb stem cells.

The existence of multipotent cells in the adult tissues and organs of those vertebrates that are capable of regeneration has been accepted for decades. Although studies of vertebrate limb regeneration have yet to identify many of the specific molecules involved in regeneration, numerous tissue grafting experiments and studies of cell lineage have contributed significantly to an understanding of the origin, activation, proliferation and cell-cell interactions of these progenitor cells. This has allowed the development of ideas about the regulation of pattern formation to restore the structure and function of lost tissues and organs. An understanding of the molecular mechanisms controlling these processes has lagged behind the dramatic advances achieved with other model organisms. However, given the intense, new research interest in stem cells over the past few years, there is good reason to be encouraged that insights about the biology of mammalian stem cells will accelerate progress in understanding the biology of regeneration in organisms that can regenerate. Advances in regeneration research will then feed back in terms of devising new strategies for therapies to induce regeneration in organisms such as humans that have traditionally been viewed as incapable of regeneration.

Animals↗