Search PubMed⌕ Search

Biomedical subjects

C Dickson

Publications and source records attributed to C Dickson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Computational modeling of entorhinal cortex.

Computational modeling provides a means for linking the physiological and anatomical characteristics of entorhinal cortex at a cellular level to the functional role of this region in behavior. We have developed detailed simulations of entorhinal cortical neurons and networks, with an emphasis on the role of acetylcholine in entorhinal cortical function. Computational modeling suggests that when acetylcholine levels are high, this sets appropriate dynamics for the storage of stimuli during performance of delayed matching tasks. In particular, acetylcholine activates a calcium-sensitive nonspecific cation current which provides an intrinsic cellular mechanism which could maintain neuronal activity across a delay period. Simulations demonstrate how this phenomena could underlie entorhinal cortex delay activity as described in previous unit recordings. Acetylcholine also induces theta rhythm oscillations which may be appropriate for timing of afferent input to be encoded in hippocampus and for extraction of individual stored sequences from multiple stored sequences. Lower levels of acetylcholine may allow sharp wave dynamics which can reactivate associations encoded in hippocampus and drive the formation of additional traces in hippocampus and entorhinal cortex during consolidation.

Acetylcholine↗
PubMed2000

An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis.

The fibroblast growth factor receptor 2 gene is differentially spliced to encode two transmembrane tyrosine kinase receptor proteins that have different ligand-binding specificities and exclusive tissue distributions. We have used Cre-mediated excision to generate mice lacking the IIIb form of fibroblast growth factor receptor 2 whilst retaining expression of the IIIc form. Fibroblast growth factor receptor 2(IIIb) null mice are viable until birth, but have severe defects of the limbs, lung and anterior pituitary gland. The development of these structures appears to initiate, but then fails with the tissues undergoing extensive apoptosis. There are also developmental abnormalities of the salivary glands, inner ear, teeth and skin, as well as minor defects in skull formation. Our findings point to a key role for fibroblast growth factor receptor 2(IIIb) in mesenchymal-epithelial signalling during early organogenesis.

Abnormalities, Multiple↗
PubMed1999

Impaired mammary gland development in Cyl-1(-/-) mice during pregnancy and lactation is epithelial cell autonomous.

A specific defect of mice lacking cyclin D1 (Cyl-1(-/-)) is impaired development of the mammary gland during pregnancy. Here we show that when tissue from Cyl-1(-/-) mammary gland was transplanted into empty mammary fat pad of wild-type mice, the abnormal phenotype was maintained, indicating that it is epithelial cell autonomous. Nevertheless, in pregnancy the early proliferative response, which is characterized by extensive side branching, still occurs in the absence of cyclin D1. However, the response is atypical due to a marked reduction in the formation of accompanying alveoli. This reduction and delay in alveolar development persists throughout pregnancy. Moreover, although prolactin synthesis and release appear to be normal, lactogenesis is severely compromised. Consistent with the appearance of numerous side branches, progesterone receptor expression was readily detected in the mammary tissue of pregnant Cyl-1(-/-) mice, although there was a significant change in the ratio of the two (A and B) receptor isoforms. In Cyl-1(-/-) mammary glands during late pregnancy there was a decrease in the abundance of total and phosphorylated Stat5a, as well as delayed onset and substantial diminution of milk protein expression. The biochemical analysis suggests that there is a cumulative delay in growth and differentiation of the mammary gland during pregnancy that results in a severely compromised gland when, at parturition, further development is curtailed by the abrupt change in hormonal milieu.

Animals↗
PubMed1999

Retinoic acid-regulated expression of fibroblast growth factor 3 requires the interaction between a novel transcription factor and GATA-4.

fgf-3 shows a complex spatial-temporal pattern of transcription during mouse development, and the gene product appears to be an important intercellular signaling molecule. Here we show that the major enhancer, which is obligatory for transcription, is composed of three elements with different properties. Both functional analyses in undifferentiated and differentiated F9 cells and characterization of DNA-protein complexes in vitro have identified the sequence motifs GTGACT(C), ATTGT, and GATA as the key transcription factor binding sites. The GTGACT(C) motif, while not essential, is required for full enhancer activity. However, binding at ATTGT is crucial for transcriptional activity and is required for cooperative binding at the proximal GATA site. The GATA binding site mediates the retinoic acid/dibutyryl cyclic AMP stimulation of transcription and correlates with the binding of Gata-4 which is induced by retinoic acid in differentiating F9 cells. The ATTGT and GATA motifs are inactive when placed separately on a minimal thymidine kinase (TK) promoter, but together they act as a strong retinoic acid-regulated enhancer. In undifferentiated F9 cells, gata-4 expression stimulates the fgf-3 promoter, whereas in differentiated F9 cells already expressing gata-4, no further increase in promoter activity was observed.

Animals↗
PubMed1999

A subset of fibroblast growth factors (Fgfs) promote survival, but Fgf-8b specifically promotes astroglial differentiation of rat cortical precursor cells.

Fibroblast growth factor-2 (Fgf-2 or basic Fgf) is known to promote the survival, proliferation, and differentiation of neural precursor cells. We have examined and compared the effects of Fgf-2 with those of Fgf-1, -4, -6, -7, -9, and -10, as well as three isoforms of Fgf-8 (-8a, -8b, and -8c), on the fate of cultured embryonic day 15 (E15) rat cortical cells. Clonal analysis, using retroviral tagging, shows that only Fgf-2, -4, and -8b can efficiently promote the survival of cortical precursor cells, the majority of which give rise to neurons. Surprisingly, and in contrast to other Fgfs, Fgf-8b also promotes astroglial differentiation of a subpopulation of these cells, which would otherwise appear to yield neurons. We also show that E15 cortical cells initially express the IIIc isoforms of Fgf-receptors (R-1,-2, and -3 but within 16 h of culturing they down regulate FgfR2-IIIc. These studies demonstrate that cortical precursor cells respond to Fgf stimulation in different ways depending on the ligand and by inference the Fgf receptors activated.

3T3 Cells↗
PubMed1998

Learning and memory difficulties after environmental exposure to waterways containing toxin-producing Pfiesteria or Pfiesteria-like dinoflagellates.

BACKGROUND: At the beginning of autumn, 1996, fish with "punched-out" skin lesions and erratic behaviour associated with exposure to toxins produced by Pfiesteria piscicida or Pfiesteria-like dinoflagellate species were seen in the Pocomoke River and adjacent waterways on the eastern shore of the Chesapeake Bay in Maryland, USA. In August, 1997, fish kills associated with Pfiesteria occurred in these same areas. People who had had contact with affected waterways reported symptoms, including memory difficulties, which raises questions about the human-health impact of environmental exposure to Pfiesteria toxins. METHODS: We assessed 24 people who had been exposed. We collected data on exposure history and symptoms, did a complete medical and laboratory assessment (13 people), and carried out a neuropsychological screening battery. Performance on neuropsychological measures was compared with a matched control group. RESULTS: People with high exposure were significantly more likely than occupationally matched controls to complain of neuropsychological symptoms (including new or increased forgetfulness); headache; and skin lesions or a burning sensation of skin on contact with water. No consistent physical or laboratory abnormalities were found. However, exposed people had significantly reduced scores on the Rey Auditory Verbal Learning and Stroop Color-Word tests (indicative of difficulties with learning and higher cognitive function), and the Grooved Pegboard task. There was a dose-response effect with the lowest scores among people with the highest exposure. By 3-6 months after cessation of exposure, all those assessed had test scores that had returned to within normal ranges. INTERPRETATION: People with environmental exposure to waterways in which Pfiesteria toxins are present are at risk of developing a reversible clinical syndrome characterised by difficulties with learning and higher cognitive functions. Risk of illness is directly related to degree of exposure, with the most prominent symptoms and signs occurring among people with chronic daily exposure to affected waterways.

Adult↗
PubMed1998

Disregulation of ocular morphogenesis by lens-specific expression of FGF-3/int-2 in transgenic mice.

FGF-3, originally named int-2, was discovered as an oncogene frequently activated in mammary carcinomas resulting from the chromosomal integration of the mouse mammary tumor virus (MMTV). Int-2 was later designated FGF-3 based on sequence homology with other members of the fibroblast growth factor (FGF) family. FGF-1 is the prototypical member of the FGF family, and is the only family member which activates all known FGF receptor isoforms. Transgenic mice expressing in the lens a form of FGF-1 engineered to be secreted show premature differentiation of the entire lens epithelium. In contrast, transgenic mice engineered to secrete FGF-2 in the lens do not undergo premature differentiation of the lens epithelium (C. M. Stolen et al., 1997, Development 124, 4009-4017). To further assess the roles of FGFs and FGF receptors in lens development, the alpha A-crystallin promoter was used to target expression of FGF-3 to the developing lens of transgenic mice. The expression of FGF-3 in the lens rapidly induced epithelial cells throughout the lens to elongate and to express fiber cell-specific proteins including MIP and beta-crystallins. This premature differentiation of the lens epithelium was followed by the degeneration of the entire lens. Since FGF-1 and FGF-3 can both activate one FGF receptor isoform (FGFR2 IIIb) that is not activated by FGF-2, these results suggest that activation of FGFR2 IIIb is sufficient to induce fiber cell differentiation throughout the lens epithelium in vivo. Furthermore, transgenic lens cells expressing FGF-3 were able to induce the differentiation of neighboring nontransgenic lens epithelial cells in chimeric mice. Expression of FGF-3 in the lens also resulted in developmental alterations of the eyelids, cornea, and retina, and in the most severely affected transgenic lines, the postnatal appearance of intraocular glandular structures.

Animals↗
PubMed1998

Toxic-Pfiesteria--surveillance for human disease in Maryland.

The presence of toxic stages of the dinoflagellate Pfiesteria piscicida and other morphologically related organisms was documented in three estuarine waterways on the lower Eastern Shore of Maryland in 1997. The Maryland Department of Health and Mental Hygiene, working closely with the local health departments, established a surveillance system to collect reports of human illnesses. Maryland's experience has formed the base on which national surveillance criteria for Estuary Associated Syndrome have been developed and regional surveillance protocols have been built. The cooperation of practicing physicians is essential to continued surveillance efforts to further delineate the extent and nature of human health effects following exposures to waters where toxic forms of these dinoflagellates are active. Physicians wishing to report persons who may have Estuary Associated Syndrome should contact their local health department. Persons wanting information or wishing to report finding lesioned fish or a fish kill in progress should call the Maryland Pfiesteria Hotline at 1- 888-584-3110.

Animals↗
PubMed1997

Fibroblast growth factor 3, a protein with dual subcellular localization, is targeted to the nucleus and nucleolus by the concerted action of two nuclear localization signals and a nucleolar retention signal.

The major isoform of fibroblast growth factor 3 (FGF3) is initiated from a CUG codon, and the resultant product is distributed to the nucleus/nucleolus and secretory pathway. This dual subcellular localization is achieved in part by the competing effects of two classical intracellular targeting signals located near the amino terminus. At the extreme amino terminus is a short stretch of 29 amino acids before a signal peptide necessary for translocation into the endoplasmic reticulum, which is next to an adjacent bipartite nuclear localization signal. The carboxyl-terminal region of FGF3 is also implicated in nuclear/nucleolar localization. We describe here the characterization of carboxyl-terminal signals by showing they are capable of directing a heterologous protein, beta-galactosidase, to the nucleus. Furthermore, appending both the amino- and carboxyl-terminal domains onto beta-galactosidase, reproduces the dual subcellular localization properties of FGF3. Nuclear uptake of FGF3 appears to be signal-mediated since it binds to karyopherin alpha, the nuclear localization signal binding subunit of a heterodimeric receptor of the nuclear import machinery. The import of FGF3 into the nucleus is energy-dependent, and the inhibition of this process has demonstrated the importance of the nucleolar retention signal in nucleoplasmic and nucleolar accumulation.

Amino Acid Sequence↗
PubMed1997

Skeletal disorders associated with fibroblast growth factor receptor mutations.

Mutations in three fibroblast growth factor receptor loci underlie several autosomal dominant skeletal disorders; these include dwarfism and various craniosynostosis syndromes affecting limb and craniofacial bone patterning. A functional analysis of several of these mutations has demonstrated that a constitutive activation of the receptor kinase is a common theme.

Bone Diseases, Developmental↗
PubMed1997

A role for fibroblast growth factor signaling in the lobuloalveolar development of the mammary gland.

The inappropriate expression of growth factors, or activating mutations of their receptors, have been implicated as causative factors in mouse and human mammary cancer. For example, it has been known for some time that three members of the fibroblast growth factor (FGF) family behave like oncogenes in virally induced mammary cancer of mice. In normal circumstances, signaling via FGF receptors is known to mediate growth, differentiation, and patterning, during embryogenesis and fetal development. A powerful approach to dissecting the roles for these signaling pathways is to determine the developmental consequences of abrogating their function in transgenic mice. In this review, we describe the use of dominant negative FGF receptors to evaluate the contribution of specific FGF signals in normal mammary gland development. These studies have revealed that normal lobuloalveolar development requires FGF signaling to the mammary epithelium, a function that is presumably usurped by MMTV in mouse mammary tumorigenesis.

Animals↗
PubMed1997

Fibroblast growth factor receptor signalling has a role in lobuloalveolar development of the mammary gland.

We have used the mouse mammary tumor virus promoter to express two dominant negative (DN) fibroblast growth factor receptor (FGFR) isoforms in the mammary epithelium of transgenic mice. While expression of DN-FGFR1(IIIc) showed no discernible phenotype, a similar kinase negative form of FGFR2(IIIb) caused a marked impairment of lobuloalveolar development. The growth retardation was apparent by mid-pregnancy and persisted in the post-partum glands. Despite the substantial underdevelopment of the mammary gland there was a measurable lactational response, but it was insufficient to properly sustain the new-born pups. These findings demonstrate that fibroblast growth factor signalling is necessary for pregnancy dependent lobuloalveolar development of the mammary gland.

Animals↗
PubMed1996

Secretion and mitogenic activity of zebrafish FGF3 reveal intermediate properties relative to mouse and Xenopus homologues.

Zebrafish (Brachyodanio rerio) Fgf-3 cDNAs expressed in COS-1 cells give rise to the heterogeneous set of secreted proteins with relative molecular masses in the range of 29-30.5 kDa. These proteins associate strongly with the extracellular matrix but are quantitatively released into the culture medium in the presence of heparin (5 micrograms/ml). Extracellular zebrafish FGF3 (ZFGF3) also contains a smaller sized component that appears to result from an amino-terminal proteolytic cleavage. These properties are similar to those described for Xenopus FGF3 (XFGF3). Receptor binding experiments indicate that ZFGF3 has a higher affinity for the IIIb rather than the IIIc isoform of FGFR2; properties that are more reminiscent of the mouse than the Xenopus homologue. Consistent with the FGF receptor binding properties, ZFGF3 shows a restricted mitogenic potential and a reduced transforming activity on NIH3T3 cells compared to XFGF3. Hybrid proteins made between Xenopus and zebrafish FGF3 implicate the C-terminal region in determining the differences in receptor potential affinities, mitogenic potency and transforming activity. Thus, ZFGF3 shows the structural and secretory properties of XFGF3, but has biological properties more akin to those of the mouse homologue.

Amino Acid Sequence↗
PubMed1996

The zebrafish Fgf-3 gene: cDNA sequence, transcript structure and genomic organization.

We report the isolation and characterization of genomic and cDNA clones encoding zebrafish fibroblast growth factor 3 (FGF3). An initial cDNA clone was generated by PCR amplification using degenerate oligo primers corresponding to a conserved region of protein found in the mouse and human homologues. Screening a cDNA library made from 30-33-h-old zebrafish embryos with this PCR product led to the isolation of two cDNA clones. Sequence analysis of the longest cDNA insert (1810 bp) revealed a 256-amino-acid (aa) orf. The central region, composed of approx. 155 aa, shares 78% identity with the analogous region of Xenopus laevis FGF3 and 72% identity with the product of the more distantly related human gene. However, the N-and C-terminal domains of zebrafish FGF3 are very different from those of other known homologues. The cDNA was used as a probe on genomic DNA to create a physical map of the locus and to isolate a genomic clone encompassing the entire coding region and 5' sequences. DNA sequencing and RNase protection analyses indicate that zebrafish Fgf-3 (ZFgf-3) is structurally analogous to the mouse gene and regulated through two different promoters. The transcription start point of the proximal promoter aligns to that of mouse promoter P3 and lies within a conserved region of sequence.

Amino Acid Sequence↗