Renal Fanconi syndrome: developmental basis for a new animal model with relevance to human disease

Using succinylacetone (SA), a metabolite of tyrosine excreted in excess by infants and children with hereditary tyrosinemia and the renal Fanconi syndrome (FS), we have investigated developmentally-related membrane transport events leading to emergence of the generalized renal tubular dysfunction seen in human FS. SA was found to impair sugar and amino acid uptake by both newborn renal tubules and 7-day renal brush-border membrane vesicles (BBMV). This impairment by SA was due in part to a slowing of substrate cotransport rate of 22Na+-entry into BBMV. Concentration-dependent uptake studies indicated SA inhibited the newborn high-affinity transport systems for sugars and amino acids. SA also caused an increase in membrane fluidity and a shift in the thermotropic transition temperature. The demonstrated dual nature of SA's effect on membrane fluidity and O2 consumption, together with the relative contribution of each component to SA-induced transport impairment helps to provide a basis for an understanding of the age-related increases in glucosuria, aminoaciduria and natriuria seen in infants with FS.     

A new model of developmental constraints as applied to the Drosophila system

Von Baer's laws of development observe that an embryo, in the course of its ontogeny, progresses through a series of forms which diverge increasingly from the embryonic forms of related species, and in an evolutionary interpretation, from those of its phylogenetic ancestors. This observation on the relation of phylogeny to ontogeny is explained by Wimsatt's (1986) "Developmental Lock" model of complex generative systems, which proposes that evolution is constrained to alter developmental programs in a manner that usually modifies or adds new complexity to pre-existent developmental functions at positions relatively "downstream" in the causal structure. If the Developmental Lock model is correct, (1) evolution should have resulted in hierarchically ordered developmental programs, and (2) the most important developmental functions in the hierarchy should be ancient. Wimsatt also suggests that developmental functions be analyzed according to a degree property called "generative entrenchment", which replaces the temporal analysis in the traditional formulation of von Baer's laws. Herein, a substantial body of data on Drosophila ontogeny is analyzed according to generative entrenchment, in order to try the effectiveness of this form of analysis, and also to empirically test these two main predictions of the Developmental Lock model. The novel analytic approach proves to be fruitful, both in generating experimental hypotheses and in ordering existing data. Moreover, data concerning the developmental functions discussed here indicate that the order of the Drosophila developmental program conforms to the predictions of Wimsatt's model with few deviations. Explanations of the anomalies are offered, along with proposals for experiments to test some of those explanations.     

Effect of olanzapine on disruptive behavior in institutionalized patients with severe intellectual disability--a case series

Considerable number of intellectual disabled people experience some form of disruptive behavior. Antipsychotics are the most common treatment for these behaviors. Numerous patients were efficiently treated with thioridazine, recently withdrawn. The authors describe a case series of "thioridazine responders" treated with olanzapine. Thirty three patients with severe intellectual disability were recruited. All patients were assessed for seven types of disruptive behavior on five point scale. Patients with severe behavior disturbances were included in treatment. The time points of assessment were at day 0, 30, 60 and 180. Twenty one patient accomplished inclusion criteria. A significant decrease occurred at day 30 for all types of behavior. Total score, self injurious behavior, compulsive and destructive behavior showed further decrease at day 60 and became stable until the end of study. Olanzapine appears to be efficacious in the treatment of disruptive behavior in the intellectually disabled and could be substitute for thioridazine treatment.     

Zebra finch as a developmental model

The domesticated zebra finch (Taeniopygia guttata) is a well‐established animal model for studying vocal learning. It is also a tractable model for developmental analyses. The finch genome has been sequenced and methods for its transgenesis have been reported. Hatching and sexual maturation in this species takes only two weeks and three months, respectively. Finch colonies can be established relatively easily and its eggs are laid at a stage earlier than in other common avian experimental models, facilitating the analysis of very early avian development. Representing the Neoaves to which 95% of all bird species belong, the finch can potentially complement two existing, Galloanserae developmental models, the chick, and quail. Here, we provide a step‐by‐step guide for how to set up a finch colony in a conventional laboratory environment. Technical tips are offered to optimize hens’ productivity and ensure a constant supply of fertilized finch eggs. Methods of handling finch eggs and embryos for subsequent embryological, cellular, or molecular analyses are also discussed. We conclude by emphasizing scientific values and cost effectiveness of maintaining a finch colony for avian developmental studies. genesis 53:669–677, 2015. © 2015 Wiley Periodicals, Inc.     

A bifurcation model for developmental processes

I have constructed, for developmental processes, a qualitative model similar to the compartment hypothesis in Drosophila, and examined its relevance to vertebrate systems. In this model a polarized “cluster” of interacting cells will be the unit for “bifurcation” of the developmental pathway into two alternative states of “locon” which is the genetic unit controlling this process. The minimum size of the cluster critical for bifurcation and the size of the emerging subclusters will be dictated by the cognate locon. This will obviate the need for an extrinsically imposed threshold of some state variable for the boundary of the two subclusters. However, the orientation of bifurcation will be determined by the polarity of the cluster. A physiological factor of competence will impose a temporal constraint to bifurcation.Thus, combinatorial binary codes for a set of locons, like those originally devised by Kauffman (1973), can be assigned to developmental pathways. One of the clusters emerging from a sequence of bifurcations will have the same code as the mother cluster. It will represent the “developmental sink”, and will not recycle through the bifurcation series originating from the initial mother cluster, because of the difference in spatio-temporal factors incorporated in the size and competence of the individual clusters. If bifurcations are prevented, the mother cluster will be forced along the pathway of the developmental sink.I have applied the model to cases in vertebrate development where commitments to developmental pathways for aperiodic or periodic segmentations may follow a linear temporal sequence, producing, in turn, subclusters of uncommitted, or stem, cells towards the more intensely polarized end of the mother cluster. Such cases include limb, somite and tail formation and several stem cell systems with a finite lifespan. I have discussed some possible experimentation which emerges from the model.     

Early developmental pathology due to cytochrome c oxidase deficiency is revealed by a new zebrafish model

Deficiency of cytochrome c oxidase (COX) is associated with significant pathology in humans. However, the consequences for organogenesis and early development are not well understood. We have investigated these issues using a zebrafish model. COX deficiency was induced using morpholinos to reduce expression of CoxVa, a structural subunit, and Surf1, an assembly factor, both of which impaired COX assembly. Reduction of COX activity to 50% resulted in developmental defects in endodermal tissue, cardiac function, and swimming behavior. Cellular investigations revealed different underlying mechanisms. Apoptosis was dramatically increased in the hindbrain and neural tube, and secondary motor neurons were absent or abnormal, explaining the motility defect. In contrast, the heart lacked apoptotic cells but showed increasingly poor performance over time, consistent with energy deficiency. The zebrafish model has revealed tissue-specific responses to COX deficiency and holds promise for discovery of new therapies to treat mitochondrial diseases in humans.     

Evolution of evolvability in a developmental model

Evolvability, the ability of populations to adapt, can evolve through changes in the mechanisms determining genetic variation and in the processes of development. Here we construct and evolve a simple developmental model in which the pleiotropic effects of genes can evolve. We demonstrate that selection in a changing environment favors a specific pattern of variability, and that this favored pattern maximizes evolvability. Our analysis shows that mutant genotypes with higher evolvability are more likely to increase to fixation. We also show that populations of highly evolvable genotypes are much less likely to be invaded by mutants with lower evolvability, and that this dynamic primarily shapes evolvability. We examine several theoretical objections to the evolution of evolvability in light of this result. We also show that this result is robust to the presence or absence of recombination, and explore how nonrandom environmental change can select for a modular pattern of variability.     

Zebrafish model systems for developmental neurobehavioral toxicology

Zebrafish offer many advantages that complement classic mammalian models for the study of normal development as well as for the teratogenic effects of exposure to hazardous compounds. The clear chorion and embryo of the zebrafish allow for continuous visualization of the anatomical changes associated with development, which, along with short maturation times and the capability of complex behavior, makes this model particularly useful for measuring changes to the developing nervous system. Moreover, the rich array of developmental, behavioral, and molecular benefits offered by the zebrafish have contributed to an increasing demand for the use of zebrafish in behavioral teratology. Essential for this endeavor has been the development of a battery of tests to evaluate a spectrum of behavior in zebrafish. Measures of sensorimotor plasticity, emotional function, cognition and social interaction have been used to characterize the persisting adverse effects of developmental exposure to a variety of chemicals including therapeutic drugs, drugs of abuse and environmental toxicants. In this review, we present and discuss such tests and data from a range of developmental neurobehavioral toxicology studies using zebrafish as a model. Zebrafish provide a key intermediate model between high throughput in vitro screens and the classic mammalian models as they have the accessibility of in vitro models and the complex functional capabilities of mammalian models. Birth Defects Research (Part C) 99:14–23, 2013. © 2013 Wiley Periodicals, Inc.     

Ancient origin of the new developmental superfamily DANGER

Developmental proteins play a pivotal role in the origin of animal complexity and diversity. We report here the identification of a highly divergent developmental protein superfamily (DANGER), which originated before the emergence of animals (approximately 850 million years ago) and experienced major expansion-contraction events during metazoan evolution. Sequence analysis demonstrates that DANGER proteins diverged via multiple mechanisms, including amino acid substitution, intron gain and/or loss, and recombination. Divergence for DANGER proteins is substantially greater than for the prototypic member of the superfamily (Mab-21 family) and other developmental protein families (e.g., WNT proteins). DANGER proteins are widely expressed and display species-dependent tissue expression patterns, with many members having roles in development. DANGER1A, which regulates the inositol trisphosphate receptor, promotes the differentiation and outgrowth of neuronal processes. Regulation of development may be a universal function of DANGER family members. This family provides a model system to investigate how rapid protein divergence contributes to morphological complexity.     

Understanding dioxin developmental toxicity using the zebrafish model

Zebrafish (Danio rerio) have advantages over mammals as an animal model for investigating developmental toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a persistent global contaminant, is the most comprehensively studied developmental toxicant in zebrafish. The hallmark responses of TCDD developmental toxicity manifested in zebrafish larvae include edema, anemia, hemorrhage, and ischemia associated with arrested growth and development. Heart and vasculature development and function are severely impaired, and jaw malformations occur secondary to inhibited chondrogenesis. The swim bladder fails to inflate, and the switch from embryonic to adult erythropoiesis is blocked. This profile of developmental toxicity responses, commonly referred to as "blue sac syndrome" because the edematous yolk sac appears blue, is observed in the larval form of all freshwater fish species exposed to TCDD at the embryonic stage of development. Components of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AHR/ARNT) signaling pathway in zebrafish have been identified and functionally characterized. Their role in mediating TCDD toxicity has been determined using morpholinos to specifically knockdown the translation of zfAHR1, zfAHR2, zfARNT1, and zfARNT2 mRNAs, respectively, and a line of zfARNT2 null mutant zebrafish has provided further insight. These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity. In addition, the growing use of molecular and genomic tools for research on zebrafish have led to advances in our understanding of the mechanism of TCDD developmental toxicity at the molecular level, including the recent finding that toxicity is not mediated by increased cytochrome P4501A (zfCYP1A) expression.