Control of segment-like patterns of gene expression in the mouse cerebellum

Oberdick, John; Schilling, Karl; Smeyne, Richard J.; Corbin, Joshua G.; Bocchiaro, Christopher M.; Morgan, James I.

doi:10.1016/0896-6273(93)90050-2

Cited by 179 publications

(135 citation statements)

References 34 publications

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“…Previously it was shown that truncations and point mutations of the L7 promoter in the context of L7-lacZ fusion genes led to perturbations of the cerebellar banding pattern in transgenic mice (16). This established that the L7 promoter is sensitive to spatial cues and must contain some representation of the banding map.…”

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confidence: 99%

“…Within the cerebellum, L7 is expressed in a dynamic temporal and spatial pattern that is manifested as parasagittal bands, or domains, of Purkinje cells (20). At least some of these bands represent functional compartments of Purkinje cells that project to specific cerebellar nuclei (16). Therefore, it is hoped that by identifying the transcription factors involved in conveying this spatial representation to L7 expression some of the principles that underlie the development of functional organization in the nervous system in general can be elucidated.…”

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confidence: 99%

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The maf Proto-oncogene Stimulates Transcription from Multiple Sites in a Promoter That Directs Purkinje Neuron-Specific Gene Expression

Kurschner

Morgan

1995

Molecular and Cellular Biology

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L7 is expressed in all adult cerebellar Purkinje cells, although during development it appears in a stereotyped spatial and temporal pattern that is manifested as parasagittal domains of neurons. Mutations of the L7 promoter in transgenic mice have established that these domains represent functional compartments of Purkinje neurons. Therefore, it is hoped that by defining the transcriptional control of the L7 gene insights into the mechanisms that control functional fate and organization in the nervous system can be gained. Fragments of the L7 promoter were introduced into a selectable reporter gene in Saccharomyces cerevisiae, and these strains were used to select for cerebellar cDNAs encoding proteins that can bind to, and activate transcription from, these elements. This assay identified the c-Maf proto-oncogene as activating transcription from two sites in the L7 promoter. A fundamental issue in developmental neurobiology is to identify the molecular and cellular mechanisms that orchestrate the genesis of functional networks of neurons from relatively homogeneous populations of precursors. One approach to this problem is to investigate the regulation of genes that define functional compartments in the nervous system. The L7 gene is expressed specifically in cerebellar Purkinje cells and retinal rod bipolar neurons (2, 17). Within the cerebellum, L7 is expressed in a dynamic temporal and spatial pattern that is manifested as parasagittal bands, or domains, of Purkinje cells (20). At least some of these bands represent functional compartments of Purkinje cells that project to specific cerebellar nuclei (16). Therefore, it is hoped that by identifying the transcription factors involved in conveying this spatial representation to L7 expression some of the principles that underlie the development of functional organization in the nervous system in general can be elucidated.Previously it was shown that truncations and point mutations of the L7 promoter in the context of L7-lacZ fusion genes led to perturbations of the cerebellar banding pattern in transgenic mice (16). This established that the L7 promoter is sensitive to spatial cues and must contain some representation of the banding map. While some promoter mutations pointed to particular classes of transcription factors as playing a role in this process, many of the DNA elements identified in the analysis did not conform to any known consensus binding sequence. Therefore, we wished to devise a strategy that would permit us to clone transcription factors from the cerebellum by using a functional assay that required prior knowledge of neither the general structure of the proteins involved nor their precise DNA-binding sites. From the practical standpoint, the screen also needed to accommodate relatively large DNA fragments to permit analysis of a significant fraction of the L7 promoter. In addition, it was reasoned that if a single copy of the L7-promoterreporter system was stably integrated into the host cell genome, it would be organized into chromatin, thereb...

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The maf Proto-oncogene Stimulates Transcription from Multiple Sites in a Promoter That Directs Purkinje Neuron-Specific Gene Expression

Kurschner

Morgan

1995

Molecular and Cellular Biology

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“…Three possible ROREs at ¹138, ¹112 and ¹80, and a RARE around at þ210 are indicated. Several other previously identified ciselements (Vandaele et al 1991;Zou et al 1994;Oberdick et al 1993;Kurschner & Morgan 1995) are also indicated.…”

Section: Resultsmentioning

confidence: 99%

“…Several known ciselements have been identified within the 5 0 -flanking region, including thyroid hormone responsive elements (TREs), AP-1 site, c-maf binding sites, E-box and POU protein binding site (Oberdick et al 1993;Zou et al 1994;Kurschner & Morgan 1995) (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, in a transient expression study using P19 cells, no cis-elements other than RORE and RARE were found to regulate the transcription, although the TR, AP-1, c-maf and POU-domain proteins have been suggested to be involved in transcriptional regulation (Strait et al 1992;Zou et al 1994;Oberdick et al 1993;Kurschner & Morgan 1995). In particular, ectopically expressed TR did not activate the Pcp-2 gene promoter in P19 cells, which differs from previous reports showing that TR activates MMTV-LTR promoter by the upstream or downstream TREs in CHO cells (Strait et al 1992;Zou et al 1994).…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional regulation of a Purkinje cell‐specific gene through a functional interaction between RORα and RAR

Mizutani¹

1997

Genes to Cells

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Increased cerebellar Purkinje cell numbers in mice overexpressing a humanBcl-2 transgene

et al. 1996

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The Purkinje cell is a primary organizer in the development of the cerebellum. Purkinje cells may provide positional information cues that regulate afferent innervation, and Purkinje cell target size controls the adult number of afferent olivary neurons and granule cells. While Purkinje cells are necessary for the survival of olivary neurons and granule cells during periods of programmed cell death, little is known about the survival requirements of Purkinje cells in vivo. To determine if Purkinje cells are subject to programmed cell death during development we have analyzed Purkinje cell numbers in two lines of transgenic mice that overexpress a human gene for bcl-2 (Hu-bcl-2). Bcl-2 is a protooncogene that inhibits apoptosis in many cell types. Overexpression of bcl-2 in vitro and in vivo rescues neurons from trophic factor deprivation or naturally occurring cell death. In the mice analyzed in this study, transgene expression is driven by the neuron-specific enolase promoter that is first expressed embryonically in most regions of the brain in one line and postnatally in the second line. We have counted Purkinje cells in three adult control mice, five early overexpressing transgenics, and three late expressing transgenics. The number of Purkinje cells in the Hu-bcl-2 transgenic mice is significantly increased above control numbers, with an increase of 43% in the embryonically overexpressing line and an increase of 27% in the postnatally overexpressing line. Because bcl-2 overexpression has been shown to rescue other neurons from programmed cell death, the increase in Purkinje cell numbers in overexpressing bcl-2 transgenics suggests that Purkinje cells undergo a period of cell death during normal development.

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Control of segment-like patterns of gene expression in the mouse cerebellum

Cited by 179 publications

References 34 publications

The maf Proto-oncogene Stimulates Transcription from Multiple Sites in a Promoter That Directs Purkinje Neuron-Specific Gene Expression

The maf Proto-oncogene Stimulates Transcription from Multiple Sites in a Promoter That Directs Purkinje Neuron-Specific Gene Expression

Transcriptional regulation of a Purkinje cell‐specific gene through a functional interaction between RORα and RAR

Increased cerebellar Purkinje cell numbers in mice overexpressing a humanBcl-2 transgene

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