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Biomedical subjects

K Herrup

Publications and source records attributed to K Herrup.

At least 73 records · Page 4Linked to original sources
PubMed1991

Renal cyst formation and multifocal neoplasia in transgenic mice carrying the simian virus 40 early region.

Simian virus 40 early region transgenic mice develop characteristic pathological abnormalities of the brain, kidney, and thymus, due to expression of large-T antigen. Earlier studies have indicated that the most consistent effect of large-T antigen expression is the formation of choroid plexus papillomas in the brain and that thymic hyperplasia and various kidney abnormalities are less frequently observed. The renal lesions reportedly consist of numerous glomerular abnormalities and tubular proliferation. Surprisingly, an analysis of 21 simian virus 40 early region transgenic mice, which were produced for this study, revealed a much higher incidence of polycystic kidney disease as well as earlier development of T-antigen-induced abnormalities. In marked contrast to earlier observations, there is an apparent reduction in the glomerular number in the affected kidneys, whereas the remaining glomeruli appear normal. The most striking feature of the T-antigen-induced renal abnormalities was extensive hyperplasia of tubular epithelial cells which was most marked in the distal tubules; all tubule segments are involved in the most severely affected animals. In most cases, cysts lined with hyperplastic epithelium were observed and papillary structures protruding from the cyst lining were evident. Multiple areas of focal neoplasia were apparent, and, in the most severely affected animals, there were areas in which tumor had replaced normal renal parenchyma. These results strongly suggest that T-antigen-induced renal cyst and tumor formation are part of the same pathological process which is initially manifested as tubular epithelial hyperplasia.

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PubMed1990

Studies of the dendritic tree of wild-type cerebellar Purkinje cells in lurcher chimeric mice.

Naturally occurring mutations are valuable tools for the study of neural development, especially when used in conjunction with the techniques of chimeric mouse production. In this study we examine the response of Purkinje cell dendrites to the altered developmental environment found in the lurcher in equilibrium with wild-type chimera. Lurcher (+/Lc) is an autosomal dominant gene that causes the cell-autonomous degeneration of all Purkinje cells of +/Lc genotype. Thus, in +/Lc in equilibrium with +/+ chimeras, only wild-type Purkinje cells survive to maturity. The number of these survivors can vary from less than 10,000 to greater than 100,000. Previous work has shown that the final ratio of presynaptic granule cells to postsynaptic Purkinje cells is increased in lurcher chimeras. On average, therefore, one might expect that each remaining Purkinje cell would experience an increased supply of afferents, and our hypothesis was that dendritic growth and/or sprouting might occur as a result. This proved incorrect and, indeed, the Purkinje cells in the lurcher chimeras show changes of a predominantly atrophic nature. Unusual morphologies are found, including variable branching density, failure of the distal dendrite to reach the pial surface, loss of isoplanarity, and the frequent appearance of large caliber, primary or secondary dendritic branches ending abruptly in "stub ends." Quantitative analysis of Golgi-Cox impregnated material reveals that in lurcher chimeras the Purkinje cell dendritic arbor is reduced by more than 60% compared to wild-type animals. We present possible explanations for this finding and consider several potential implications.

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PubMed1990

Patterns of cell lineage in the cerebral cortex reveal evidence for developmental boundaries.

Experimental aggregation chimeric mice offer a perspective on cell lineage relationships that is complementary to that of prospective tracing methods such as dye injections or recombinant retroviruses. To create a lineage map of cerebral cortex, the position and genotype of cortical neurons in three-dimensional space were reconstructed with the aid of a computer-assisted mapping system. Chi-square statistical analyses indicate that the spatial distribution of cell lineages in the cerebral cortex is highly nonrandom. When individual dimensions are analyzed separately, a high degree of order is found in the spatial distribution of neuronal genotype ratios in the anterior-posterior dimension but not in the medial-lateral dimension. This suggests an arrangement of lineage-related neurons into "slabs" or "stripes" of cells that are organized in the plane perpendicular to the neuraxis. Additionally, a highly significant variation in genotype ratios was found in the radial dimension (i.e., among cortical cell layers). These data suggest the hypothesis that separate sets of progenitor cells give rise to the superficial and deep layers of cortex. Taken together, our data are consistent with a picture of the developing nervous system in which early developmental restrictions to cell mixing set up boundaries that may be of considerable developmental genetic importance.

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PubMed1990

Cell loss in the inferior olive of the staggerer mutant mouse is an indirect effect of the gene.

Staggerer (sg) is an autosomal recessive mutation in mouse that causes severe cerebellar atrophy. In this mutant, the Purkinje cell (PC) number is reduced by about 75% and the remaining Purkinje cells have a reduced dendritic arbor and an ectopic location. Previous analysis of staggerer chimeras has demonstrated that the Purkinje cell phenotypes are all direct consequences of the cell-autonomous action of the staggerer gene. The two major afferents to the Purkinje cell are also affected. Virtually all of the granule cells die by the end of the first postnatal month. This death, however, has been shown to be an indirect consequence of mutant gene action. The second major afferent system is from the cells of the inferior olive that project to the main trunks of the Purkinje cell dendrite via the climbing fiber system. Quantitative studies of cell number in the inferior olive have shown that the number of cells is reduced by about 62% in adult sg/sg mutants. We report here the results of our quantitative analysis of three staggerer chimeras. beta-glucuronidase activity was used as an independent cell marker. Our findings demonstrate that inferior olive cell death in staggerer mutant mice is an indirect effect of staggerer gene action. Thus, as for the granule cells, the loss of olivary neurons most likely results from a target related cell death.

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PubMed1989

Numerical matching in the mammalian CNS: lack of a competitive advantage of early over late-generated cerebellar granule cells.

In this report we use postnatal 3H-thymidine injections to test whether granule cells that are generated early in postnatal cerebellar development and whose axons have access to their Purkinje cell target beginning in the first postnatal week have an advantage over granule cells generated 9 days later in the competition for target-related stabilization. In the wild-type mouse, 3-5% of the adult granule cell population is labeled by injection of 3H-thymidine at either postnatal day 4 (P4) or P13. In the lurcher mutant, however, over 40% of the surviving granule cells are labeled by P4 injection while less than 1% are labeled after a P13 injection. Together, these results suggest that time of target contact is a critical factor in the competition for neuronal survival. The results from the lurcher chimeras, however, reveal that the situation is likely to be more complicated. In all chimeras examined, with target sizes ranging from 3 to 108% of wild type, equivalent numbers of granule cells were labeled at P4 and P13. These data lead to the contradictory conclusion that, in this experimental situation, early generated granule cells do not have a competitive advantage over later-generated granule cells. The results are discussed in terms of various models of target stabilization. We propose that, of the various hypotheses, our results are best explained by postulating two distinct mechanisms for developmental cell death. Supporting evidence for this hypothesis from other neuronal systems is also briefly reviewed.

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PubMed1989

Numerical matching between granule and Purkinje cells in lurcher chimeric mice: a hypothesis for the trophic rescue of granule cells from target-related cell death.

Previous studies of wild-type mice or mutant-wild-type mouse chimeras using the neurological mutant staggerer have supported a numerical matching hypothesis for target-related cell death. However, analyses of chimeras of a second neurological mutant, lurcher, have suggested that there may be significant flexibility in the relationship between the numbers of pre- and postsynaptic neurons. Whereas in staggerer chimeras there is a strict proportionality between the number of cerebellar granule cells and their postsynaptic target, the Purkinje cells, in lurcher chimeras, Wetts and Herrup (1983) report a relative increase in granule cell survival. We have reexamined the numerical matching between Purkinje and granule cells in an additional 5 lurcher----wild-type and 4 wild-type----wild-type chimerase. Our findings confirm and extend the results of the previous study to show that there is a close correlation between the number of granule and Purkinje cells in +/Lc chimeras, but for any given number of Purkinje cells in the +/Lc chimeras, more granule cells survive than in staggerer chimeras or inbred mouse strains. Whereas the ratio of granule to Purkinje cells in staggerer chimeras or inbred mouse strains is constant across all target sizes, in +/Lc chimeras the ratio of granule cells to Purkinje cells increases as the number of target neurons decreases. It seems likely that the increased granule cell survival is somehow related to the delayed degeneration of the +/Lc fraction of target cells in the +/Lc chimeras. Among the possible explanations for the observed results, we favor the hypothesis that a trophic factor is produced in +/Lc chimeras in response to the deafferentation of Purkinje cells that is capable of rescuing granule cells from target-related cell death. Our preference is based, in part, on observations of the state of the dendritic tree of the wild-type Purkinje cells that survive in +/Lc chimeras (Caddy et al., 1986).

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PubMed1988

Cell surface expression and alloantigenic function of a human class I MHC heavy chain gene (HLA-B7) in transgenic mice.

We have introduced the gene encoding the heavy chain of the human MHC class I Ag HLA-B7 into transgenic mice. The gene was shown to be expressed at both the RNA and protein level. Cell surface HLA-B7 was detected on whole spleen cells by immunoprecipitation and on purified T cells by flow cytometry (FACS). Normal mice immunized with H-2-syngeneic B7-transgenic spleen cells generated CTL capable of killing transgenic cells and B7-expressing human JY cells. Anti-HLA mAb blocked the killing of JY cells. These results indicate that the human class I Ag HLA-B7 can be expressed at the surface of transgenic spleen cells in the absence of human beta 2-microglobulin, and that a significant fraction exists in a form recognizable by nontransgenic CTL as a major histocompatibility Ag unrestricted by H-2.

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PubMed1988

Meiotic expression of human ornithine transcarbamylase in the testes of transgenic mice.

In an attempt to use mouse metallothionein-I (mMT-I) regulatory sequences to direct expression of human ornithine transcarbamylase in the liver of transgenic animals, fusion genes joining either 1.6 kilobases or 185 base pairs of the mMT-I regulatory region to the human ornithine transcarbamylase protein-coding sequence were used to produce transgenic mice. In mice carrying the fusion gene with 1.6 kilobases of the mMT-I 5'-flanking sequences, transgene expression was observed in a wide range of tissues, but, unexpectedly, expression in liver was never observed. Surprisingly, in mice carrying the fusion gene regulated by only 185 base pairs of the mMT-I 5'-flanking sequences, the transgene was expressed exclusively in male germ cells during the tetraploid, pachytene stage of meiosis.

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PubMed1988

The control of neuron number.

In comparing strategies used to control neuron number, we find it useful to view nervous system development as occurring in three phases. The phases overlap--each is a process, not an event. The first phase is the development of a genetic nervous system. This is a nervous system of simple genetic intention, not a blueprint or pile of bricks. Its characteristics are abstract: How many neurons in this stem cell destined to produce, which cells are programmed to die, how much target does this cell need to survive. At the level of the individual, the genetic nervous system is essentially fixed, but over generations it is fluid. As this genetic intent interacts within a world of cells, a real brain appears. A new set of rules only tacitly present in the genome is expressed--the embryonic nervous system emerges. The interaction of its parts defines the shape and size of the nervous system. Neuron numbers are adjusted interactively by changes in proliferative potential and the severity of cell death. Cell fates are established in part through interactions with other cells and with hormones. Glial cell numbers are adjusted to match the neuron populations. This phase of brain development is what the embryologist sees under the microscope. The third and final phase of development begins when the brain starts to function and the animal starts to deal with its world. Small changes in neuron number may occur during this period, but these changes are generally of minor functional importance. At this point, the smaller elements of neuronal organization are refined in shape, number, and distribution. Axons are lost or rearranged; dendrites grow, branch, and retract; synapses are fine-tuned; and finally, receptor densities and transmitter titres are adjusted. Some of these interactions and numerical adjustments continue until the animal dies.

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PubMed1987

Regional differences in cytoarchitecture of the weaver cerebellum suggest a new model for weaver gene action.

This paper examines the structure and cytoarchitecture of the cerebellum of the weaver mutant mouse with particular emphasis on regional differences along the mediolateral and anterior-posterior axes. We have uncovered several, previously undescribed features of the weaver cerebellar phenotype. Perhaps the most dramatic example of our findings is the severe disruption of the folial structure of the hemispheres of the weaver cerebellum. A dorsal overgrowth of tissue occurs in the hemispheres that forms a finger-like projection superficial to an atrophic but structurally more normal cerebellar mass underneath. While this folial abnormality is most evident in the homozygote (wv/wv) the antecedents of its appearance are already apparent in the heterozygote (+/wv). At the level of the cytoarchitectonics of the mutant brain, we find substantial variation in the positioning, numbers and density of both Purkinje and granule cells. As a whole, Purkinje plus Golgi II cell numbers are down by over 40%, but this reduction occurs almost exclusively in the medial half of the cerebellum. The hemispheric region contains a nearly normal number of cells per sagittal section (although their positions are predominantly incorrect). The granule cells also show numerical variation; they are nearly absent at the midline, but a substantial number of them survive in the lateral cerebellar cortex. In the paraflocculus, for example, granule cells can be observed in a modest internal granule cell layer as late as 38 postnatal days. These results are discussed in terms of a model of wv gene action in which we propose that the effect of the mutation is a general disruption of cellular distribution in the cerebellar cortex, affecting both Purkinje and granule cells and beginning prenatally.

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PubMed1987

Numerical matching during cerebellar development: quantitative analysis of granule cell death in staggerer mouse chimeras.

Cell death is a common yet puzzling feature of the development of many populations of neurons in the CNS. In the invertebrate phyla, such death is often preprogrammed; by contrast, in vertebrates, the best studied examples of histogenetic cell death are influenced by interactions among the neurons and their target. One attempt to explain this seemingly wasteful scheme of development has led to the hypothesis that this target-related cell death allows 2 populations of cells, which develop in isolation, to come into numerical and functional balance and hence to provide an epigenetic "buffer" mechanism to accommodate developmental variations. In the current study we have examined the extent to which the cell death observed in the cerebellar granule cell population serves to numerically match these neurons with their primary postsynaptic target, the Purkinje cell. Staggerer chimeras were made by aggregating 8-cell staggerer embryos with embryos of wild-type genotype. The cerebella of the resulting animals developed with widely varying numbers of normal (wild-type) Purkinje cell targets. Although staggerer Purkinje cells were present in the chimeric brains, these cells are intrinsically deficient in their normal developmental program (in the mutant, because of this deficiency, 100% of the granule cells die). Both granule cells and Purkinje cells were counted in chimeras and several wild-type mice. The results reveal that the number of granule cells present in these brains has a linear relationship with the number of Purkinje cells, and that the line connecting the points intersects the Y-axis close to the origin. These observations suggest that numerical matching is an important function of target-related cell death in the granule cell population.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMed1986

Cell lineage relationships in the development of the mammalian CNS: role of cell lineage in control of cerebellar Purkinje cell number.

This report continues our studies of the cell lineage relationships among the cells of the cerebellar Purkinje cell population. It examines the question of whether there are cell autonomous factors that regulate cell number during mammalian CNS development. Experimental aggregation chimeras were made by the joining of two embryos, one wild-type, one lurcher in genotype; both embryos were of C57BL/6 genetic background. Since all Purkinje cells of +/Lc genotype will degenerate, only wild-type Purkinje cells remain in the cerebellar cortex of the adult chimeras. The number of remaining cells does not vary uniformly from zero (the lurcher value) to wild-type (92,000 for C57BL/6). Rather the cells occur in numerical quanta that represent developmental clones of cells. In an earlier work, the Purkinje cell population of the C3H/HeJ inbred strain was shown to consist of eight such clones in each cerebellar half. Each C3H/HeJ clone contains 10,200 Purkinje cells. Evidence is presented in the present study that the Purkinje cells of the C57BL/6 strain, exist in 10 clones, of 9200 cells per half cerebellum. The findings suggest that a clonal organization exists in the Purkinje cell population of at least two inbred strains of mice, that differences in adult neuronal number can be due to either the number of clones present or the size of each individual clone (i.e., the number of cells per clone), and that the number of cells in a clone appears to be an autonomous property of the lineage itself and hence, presumably, of the progenitor cell that founded the clone.

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PubMed1986

Cell lineage dependent and independent control of Purkinje cell number in the mammalian CNS: further quantitative studies of lurcher chimeric mice.

Recent quantitative studies of lurcher chimeric mice have shown that the adult population of cerebellar Purkinje cells can properly be described as a small number of developmental clones of cells. The clones are not seen as patches of contiguous neurons; rather, the cells of any one clone distribute throughout the half-cerebellum that contains them, intermingling extensively with the Purkinje cells of other linkages. Lurcher----wild-type chimeras were analyzed using the cell autonomous Purkinje-cell-lethal mutant, lurcher (+/Lc), as a cell marker. Cell counts from these chimeras revealed that the number of surviving Purkinje cells was always an integral multiple of a unit clone size. These numerical quanta are the evidence for the existence of Purkinje cell developmental clones. When two different inbred strains of mouse were compared (C3H/HeJ and C57BL/6), the resulting clonal analysis showed that the unit clone size (i.e., the number of Purkinje cells in one quantum) is an autonomous property of the lineage and hence, presumably, intrinsic to the progenitor cell that founded it. The current study uses the lurcher chimeric mouse system to examine the cell lineage relationships among the Purkinje cells of a third inbred strain of mouse, AKR/J. The data both support and extend our previous studies. Quantitative analysis reveals that the Purkinje cells of this strain also exist in clones, and the size of these clones is also strain-specific. The number of cells in a single clone (7850), however, is different from either C3H/HeJ (10,200) or C57BL/6 (9200). The fact that this value is so highly polymorphic among the inbred strains of mouse makes it likely that, rather than being a function of different alleles at a single genetic locus, clone size may well represent a multifactorial (but still cell-autonomous) property of developing Purkinje cells. Additional results from a single chimeric animal suggest strongly that clone number (i.e., the number of progenitors selected to found the population) is not strain-specific but results instead from cell:cell interactions during early nervous system formation.

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PubMed1984

Cell lineage relationships in the development of the mammalian CNS. I. The facial nerve nucleus.

Genetically mosaic animals are valuable tools in the study of cell lineage relationships during development. The work described here is a quantitative analysis of large motor neurons of the facial nerve nucleus of the mouse. Aggregation chimeric mice were made from embryos which differed at the structural locus for the enzyme beta-glucuronidase. This difference is an intrinsic property of each cell and is easily detected by histochemical means. The numbers of cells in each of 10 facial nuclei from six glucuronidase chimeras were determined and each cell was scored for its embryo of origin using the glucuronidase marker. Unlike cerebellar Purkinje cells, this analysis revealed no evidence of numerical quanta of invariant size in the facial nucleus. Determination of the fraction of the total cells comprised by the descendants of each embryo, however, revealed evidence of quanta. These values suggest that the neurons of each facial nucleus descend from 12 progenitors. In agreement with similar calculations performed on Purkinje cells, the facial nucleus progenitors appear to be selected as the sole source of the facial nucleus neurons some time during the neural plate to neural groove stage of development. The absence of rigidly specified numerical quanta in the nucleus suggests that factors extrinsic to these cells contribute to the final adult number of neurons.

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PubMed1984

Role of staggerer gene in determining cell number in cerebellar cortex. II. Granule cell death and persistence of the external granule cell layer in young mouse chimeras.

Staggerer mice (sg/sg) have a severe ataxia correlated with cerebellar Purkinje cell anomalies and granule cell death. Previous studies of adult staggerer----wild-type chimeric mice have revealed that the mutant Purkinje cell defects visible in the light microscope (small size, ectopia and reduced number) are intrinsic properties of sg/sg Purkinje cells, while the granule cell death observed in the mutant is not an intrinsic property of sg/sg granule cells. In this report we continue the study of granule cell death and examine the phenotype, observed in staggerer mutants, of the developmental persistence of the external granular layer (EGL). Four staggerer----wild-type mouse chimeras were examined at 16 or 17 days of postnatal age. Most showed intermediate amounts of granule cell pycnosis and all showed intermediate expression of EGL persistence. There was little correlation observed between the amount of granule cell pycnosis and either the genotype of the immediately underlying Purkinje cells, or the proportion of staggerer cells in the chimera as a whole (determined by the genotype ratio of other brain regions and by coat melanocytes). While the presence or absence of an EGL did not correlate with the genotype of the immediately adjacent Purkinje cells, there was good agreement between the extent of persistence of the EGL and the overall contribution of staggerer cells to the chimera. The results suggest that the intermediate numbers of granule cells observed in adult staggerer chimeras are the result of both reduced granule cell genesis and increased pruning by cell death. The findings are further discussed in terms of two possible models of staggerer gene action.

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PubMed1984

Cell lineage relationships in the development of the mammalian CNS. II. Bilateral independence of CNS clones.

This report contains additional observations on the cell lineage relationships of the motor neurons of the facial nucleus and of the cerebellar Purkinje cells of the mouse. These cell populations were quantitatively analyzed in the mosaic brains of experimental aggregation chimeras. The cell markers used to perform the analysis were (1) staining differences in beta-glucuronidase enzyme activity due to differences at the Gus locus on chromosome 5 and (2) self-destruction of all Purkinje cells of one genotype due to the cell autonomous action of the lurcher gene on chromosome 6. Of 6 animals examined in the Purkinje cell study, 5 showed left/right differences in the clonal composition of the cerebellum. Of 4 animals examined in the facial nucleus study, all 4 showed differences in genotype ratio. These results imply that the event that defines the selection of the progenitor cells for each of these two cell types is, in fact, two bilaterally independent events. This is consistent with the pictures of the early nervous system derived from embryological observations. The implication of these findings for cell mixing during development is discussed.

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PubMed1983

Direct correlation between Purkinje and granule cell number in the cerebella of lurcher chimeras and wild-type mice.

This study quantitatively examines the developmental relationship between Purkinje cell and granule cell neurons in the cerebellum. Lurcher chimeric mice were used as a model system since target size (i.e. the number of Purkinje cells) can be varied genetically and its effect on granule cell number can be examined. The validity of this model is supported by our previous studies showing that the death of all the Purkinje cells in +/Lc mice is a direct effect of Lc gene action while the loss of 90% of the granule cells is a secondary consequence of some defect extrinsic to the granule cells, most likely the Purkinje cell loss. In the present study of 3 +/Lc mice, 4 strains of wild-type mice and 4 lurcher chimeras, the number of granule cells was directly correlated with the number of Purkinje cells. In wild-type mice, there is a constant ratio of about 175 granule cells for each Purkinje cell. These findings provide suggestive evidence that 'numerical matching' occurs between the presynaptic granule cell population and its postsynaptic target, the Purkinje cell. The quantitative relationships revealed in the chimeric animals compared with the non-chimeric values lead us to propose a model in which the number of granule cells is a function of at least two factors: the initial number of Purkinje cells and the length of time each Purkinje cell is present during a 'critical period' of granule cell development.

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