Biomedical subjects

David J Price

Publications and source records attributed to David J Price.

41 records · Page 3Linked to original sources

PubMed2002

Pax6; a pleiotropic player in development.

Pax6 is a transcription factor essential for the development of tissues including the eyes, central nervous system and endocrine glands of vertebrates and invertebrates. It regulates the expression of a broad range of molecules, including transcription factors, cell adhesion and short-range cell-cell signalling molecules, hormones and structural proteins. It has been implicated in a number of key biological processes including cell proliferation, migration, adhesion and signalling both in normal development and in oncogenesis. The mechanisms by which Pax6 regulates its downstream targets likely involve the use of different splice variants and interactions with multiple proteins, allowing it to generate different effects in different cells. Extrapolation to developmental transcription factors in general suggests that variation in the nature of individual factors is likely to contribute to the emergence of differences between tissues.

Animals↗

PubMed2002

Etr-r3/mNapor, encoding an ELAV-type RNA binding protein, is expressed in differentiating cells in the developing rodent forebrain.

The gene encoding human neuroblastoma apoptosis-related RNA binding protein (NAPOR) has rat and mouse homologues, Etr-r3 and mNapor, cloned recently by ourselves and others. Etr-r3/mNapor is transcribed in embryonic brain but its detailed expression patterns are unknown. It has been hypothesised that its expression coincides with the occurrence of programmed cell death, but existing expression data are insufficient to evaluate this possibility. We used northern blots and in situ hybridisation to show that Etr-r3/mNapor is expressed by most postmitotic differentiating cells throughout the forebrain during embryogenesis and the first weeks of postnatal life. Expression is particularly high in the developing cerebral cortex, in nuclei of the ventral telencephalon, in dorsal thalamus and in hypothalamus. In contrast, Etr-r3/mNapor is expressed by very few cells in proliferative regions, where cell death rates are highest.

Animals↗

PubMed2002

Layer-specific thalamocortical innervation in organotypic cultures is prevented by substances that alter neural activity.

Cortical layer IV is the major target of thalamocortical axons and many previous studies have shown that the development of this layer-specific innervation can be modelled in vitro by organotypic cocultures of thalamus and cortex. The mechanisms causing thalamic axons to terminate in layer IV are unknown. We used these in vitro models to test the possibility that neural activity plays a part in this termination process by adding substances that raise or lower levels of neural activity to the cocultures. We found that addition of tetrodotoxin or 2-amino-5-phosphonovalerate, to block activity, or potassium, to raise it, all interfered with termination in layer IV. These findings suggest that termination in layer IV requires neural activity at an appropriate level in the thalamocortical system. They also add support to recent findings that show that the importance of neural activity in development may extend to an earlier period than thought previously, to include the correct targeting of axons as well as the later refinement of connections.

2-Amino-5-phosphonovalerate↗

PubMed2002

Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors.

In the proliferative zone of the developing cerebral cortex, multipotential progenitors predominate early in development and divide to increase the progenitor pool. As corticogenesis progresses, proportionately fewer progenitors are produced and, instead, cell divisions yield higher numbers of postmitotic neurones or glial cells. As the switch from the generation of progenitors to that of differentiated cells occurs, the orientation of cell division alters from predominantly symmetrical to predominantly asymmetrical. It has been hypothesised that symmetrical divisions expand the progenitor pool, whereas asymmetrical divisions generate postmitotic cells, although this remains to be proved. The molecular mechanisms regulating these processes are poorly understood. The transcription factor Pax6 is highly expressed in the cortical proliferative zone and there are morphological defects in the Pax6(Sey/Sey) (Pax6 null) cortex, but little is known about the principal cellular functions of Pax6 in this region. We have analysed the cell-cycle kinetics, the progenitor cleavage orientation and the onset of expression of differentiation markers in Pax6(Sey/Sey) cortical cells in vivo and in vitro. We showed that, early in corticogenesis at embryonic day (E) 12.5, the absence of Pax6 accelerated cortical development in vivo, shortening the cell cycle and the time taken for the onset of expression of neural-specific markers. This also occurred in dissociated culture of isolated cortical cells, indicating that the changes were intrinsic to the cortical cells. From E12.5 to E15.5, proportions of asymmetrical divisions increased more rapidly in mutant than in wild-type embryos. By E15.5, interkinetic nuclear migration during the cell cycle was disrupted and the length of the cell cycle was significantly longer than normal in the Pax6(Sey/Sey) cortex, with a lengthening of S phase. Together, these results show that Pax6 is required in developing cortical progenitors to control the cell-cycle duration, the rate of progression from symmetrical to asymmetrical division and the onset of expression of neural-specific markers.

Animals↗

PubMedDate not supplied

Apparent lack of CYP1A response to high PCB body burdens in fish from a chronically contaminated PCB site.

Chronic exposure to organic contaminants such as polychlorinated biphenyls (PCBs) can lead to the development of resistance to these chemicals, a condition associated with reduced response of CYP1A1, a pollutant-inducible biomarker. We measured CYP1A activity (ethoxyresorufin o-deethylase, EROD) and PCB concentrations in feral fish from the Town Branch/Mud River system (Logan County, KY), a stream historically contaminated with PCBs and partially remediated. As a first step in evaluating the possible development of resistant populations in this system, we measured CYP1A expression and PCB body burdens in resident fish from sites we previously characterized as containing biologically significant levels of CYP1A inducing compounds. Mean PCB concentrations in edible flesh ranged from 75.2 to 16.7 microg/g in fish collected from Town Branch remediated sites and were relatively low (1.23 microg/g) in Town Branch reference site fish. However, hepatic CYP1A activity was similar among individuals of most species collected from reference and contaminated/remediated sites. The absence of elevated CYP1A levels in resident fish species despite the presence of significant PCB body burdens may indicate these fish have developed reduced sensitivity to CYP1A induction, a condition associated with acquired resistance to toxicants.

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