BAC-mediated gene-dosage analysis reveals a role for Zipro1 (Ru49/Zfp38) in progenitor cell proliferation in cerebellum and skin

Yang, Xiangdong; Wynder, Christopher; Doughty, Martin L.; Heintz, Nathaniel

doi:10.1038/11896

Cited by 112 publications

(73 citation statements)

References 49 publications

(52 reference statements)

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“…The use of transgenic mice has been beneficial to study the effect of overexpression or copy number variation of a single gene 24,25 or a group of genes involved in segmental aneuploidy. 26,27 While haploinsufficiency of RAI1 results in the majority of clinical features of SMS, its role in the reciprocal duplication 17p11.2 syndrome is not clearly understood.…”

Section: Discussionmentioning

confidence: 99%

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

et al. 2008

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The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith-Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17 þ , involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1 41.5-fold and 42-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cagetop hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.

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Section: Discussionmentioning

confidence: 99%

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

et al. 2008

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“…9A). Furthermore, the expression levels of the transcription factors Zic1 (Aruga et al, 1998) and to a lower extent Zipro1 (Yang et al, 1999), which are expressed in vivo in both the EGL and IGL, were also induced by PC3. Similarly, the level of NeuroD mRNA, whose expression is needed for differentiation and is maintained in mature granule cells (Lee, 1996;Miyata et al, 1999), was also slightly increased (Fig.…”

Section: Pc3 Acts Upstream Of Math1 and Controls Its Transcriptionmentioning

confidence: 99%

Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

Canzoniere¹,

Farioli-Vecchioli

Conti³

et al. 2004

J. Neurosci.

101

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Growing evidence indicates that cell cycle arrest and neurogenesis are highly coordinated and interactive processes, governed by cell cycle genes and neural transcription factors. The gene PC3 (Tis21/BTG2) is expressed in the neuroblast throughout the neural tube and inhibits cell cycle progression at the G 1 checkpoint by repressing cyclin D1 transcription. We generated inducible mouse models in which the expression of PC3 was upregulated in neuronal precursors of the neural tube and of the cerebellum. These mice exhibited a marked increase in the production of postmitotic neurons and impairment of cerebellar development. Cerebellar granule precursors of PC3 transgenic mice displayed inhibition of cyclin D1 expression and a strong increase in the expression of Math1, a transcription factor required for their differentiation. Furthermore, PC3, encoded by a recombinant adenovirus, also induced Math1 in postmitotic granule cells in vitro and stimulated the Math1 promoter activity. In contrast, PC3 expression was unaffected in the cerebellar primordium of Math1 null mice, suggesting that PC3 acts upstream to Math1. As a whole, our data suggest that cell cycle exit of cerebellar granule cell precursors and the onset of cerebellar neurogenesis are coordinated by PC3 through transcriptional control of cyclin D1 and Math1, respectively.

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“…Unlike the knock-in approach, the BAC transgenic approach does not require the lengthy process of germline transmission and cross-breeding, and may even produce a stronger than knock-in expression of the transgene in mice with multiple copies of the transgene. Because of these benefits, the BAC transgenic technology has been increasingly applied to characterize the transcriptional regulation of gene expression (Reizis and Leder, 2001;Yu et al, 1999), label specific cell types (Chi et al, 2003), confirm the functionality of genetic mutations by in vivo complementation (Antoch et al, 1997;Probst et al, 1998), and reveal novel genetic functions (Heintz, 2000;Yang et al, 1999). Despite its expression fidelity and convenience, several issues are associated with this approach.…”

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confidence: 99%

BAC transgenic expression efficiency: bicistronic versus ATG‐fusion strategies

Lin

Yanagimoto

Tsai

2007

Genesis

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Bacterial artificial chromosome (BAC)‐based transgene can be expressed bicistronically with the target gene or fused to its translation start codon. To compare the transgene expression efficiencies of these two methods, mice were created that expressed green fluorescent protein (GFP) from the genomic locus of nucleostemin using the bicistronic (NSiGFP) or the ATG‐fusion approach (NSmGFP). Three lines with 1, 2, and 4 copies of the NSiGFP transgene, and two lines with 1 copy of the NSmGFP transgene were generated. Of the three NSiGFP lines, only the 4‐copy line can match the NSmGFP lines in their GFP protein expression levels. Analyses of the GFP and nucleostemin RNA transcript levels exclude IRES inefficiency and suggest premature termination of the bicistronic message as the cause for low GFP expression in the NSiGFP mice. This work provides important information for designing BAC transgenics when the transgene expression level is crucial. 45:647–652, 2007. © 2007 Wiley‐Liss, Inc.

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BAC-mediated gene-dosage analysis reveals a role for Zipro1 (Ru49/Zfp38) in progenitor cell proliferation in cerebellum and skin

Cited by 112 publications

References 49 publications

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

Dual Control of Neurogenesis byPC3through Cell Cycle Inhibition and Induction ofMath1

BAC transgenic expression efficiency: bicistronic versus ATG‐fusion strategies

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