Complex phenotype of mice homozygous for a null mutation in the <i>Sp4</i> transcription factor gene

Göllner, Heike; Bouwman, Peter; Mangold, Monika; Karis, Alar; Braun, Harald; Rohner, Iris; Rey, Adriana del; Besedovsky, Hugo-Oskar; Meinhardt, Andreas; Broek, M. van den; Cutforth, Tyler; Grosveld, Frank; Philipsen, Sjaak; Suske, Guntram

doi:10.1046/j.1365-2443.2001.00455.x

Cited by 54 publications

(56 citation statements)

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“…Although Sp family members are coexpressed broadly, developmental defects exhibited by subtypespecific knockout mice indicate that their functions may only partially overlap (Supp et al, 1996;Marin et al, 1997;Bouwman et al, 2000;Nguyêñ-Trân et al, 2000;Göllner et al, 2001;van Loo et al, 2003). Recent studies indicate Sp2 is required for early embryonic development in mice and zebrafish (Baur et al, 2010;Xie et al, 2010), and Sp2 overexpression in skin stem cell and progenitor populations is oncogenic (Kim et al, 2010).…”

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confidence: 99%

Neural development is dependent on the function of specificity protein 2 in cell cycle progression

et al. 2013

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SUMMARYFaithful progression through the cell cycle is crucial to the maintenance and developmental potential of stem cells. Here, we demonstrate that neural stem cells (NSCs) and intermediate neural progenitor cells (NPCs) employ a zinc-finger transcription factor specificity protein 2 (Sp2) as a cell cycle regulator in two temporally and spatially distinct progenitor domains. Differential conditional deletion of Sp2 in early embryonic cerebral cortical progenitors, and perinatal olfactory bulb progenitors disrupted transitions through G1, G2 and M phases, whereas DNA synthesis appeared intact. Cell-autonomous function of Sp2 was identified by deletion of Sp2 using mosaic analysis with double markers, which clearly established that conditional Sp2-null NSCs and NPCs are M phase arrested in vivo. Importantly, conditional deletion of Sp2 led to a decline in the generation of NPCs and neurons in the developing and postnatal brains. Our findings implicate Sp2-dependent mechanisms as novel regulators of cell cycle progression, the absence of which disrupts neurogenesis in the embryonic and postnatal brain.

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Section: Introductionmentioning

confidence: 99%

Neural development is dependent on the function of specificity protein 2 in cell cycle progression

et al. 2013

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“…7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.In our endeavor to understand the function of HF-1b/Sp4 in the nervous system, we have undertaken a genetic rescue strategy to generate hypomorphic Sp4 alleles. Targeted transgenes were designed to enable the restoration of the expression of the Sp4 gene in the context of its endogenous locus in order to rescue any abnormal in vivo phenotypes.…”

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Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

et al. 2004

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Hf-1b/Sp4, a member of the Sp1 family of transcription factors, is expressed restrictively in the developing nervous system and most abundantly in adult hippocampus in mice. Here, we report the generation of hypomorphic Sp4 allele mice, in which the Sp4 deficiency can be rescued by the expression of Cre recombinase. Vacuolization was detected in the hippocampal gray matter of the mutant Sp4-deficient mice. Expression analysis of Sp4 mutant hippocampi revealed an age-dependent decrease in neurotrophin-3 expression in the dentate granule cells. Hypomorphic Sp4 mutant mice displayed robust deficits in both sensorimotor gating and contextual memory. The restoration of Sp4 expression, via a Cre-dependent rescue strategy, completely rescued all the observed molecular, histological and behavioral abnormalities. Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders. Molecular Psychiatry ( Keywords: transcription factor; hippocampus; schizophrenia; mouse model; behavior; Cre recombinase; genetic rescue Sp1, the prototypal member of the Sp family of transcription factors, has been demonstrated to be essential for embryogenesis. 1 The reduction of its expression in heterozygous Sp1 mice causes a decreased expression of its downstream target gene, MeCP2, whose mutation is responsible for Rett syndrome, a human neurodevelopmental disorder. 2 Recently, Sp1 and other glutamine-rich transcription factors have been implicated in the pathogenesis of neurodegenerative diseases. 3,4 Sp4, also known as HF1b, is another member of the Sp1 family of transcription factors. Sp1 and Sp4 proteins have approximately 50% homology in primary structure, which consists of two glutamine-rich transcription activation domains and Cterminal three zinc-finger DNA binding domains. 5 Both proteins recognize the same DNA binding motif with similar affinity, and often functionally substitute for each other in vitro. 6 Previously, we found that HF-1b/ Sp4 null mutant mice suffer from cardiac arrhythmia and sudden death. 7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.In our endeavor to understand the function of HF-1b/Sp4 in the nervous system, we have undertaken a genetic rescue strategy to generate hypomorphic Sp4 alleles. Targeted transgenes were designed to enable the restoration of the expression of the Sp4 gene in the context of its endogenous locus in order to rescue any abnormal in vivo phenotypes. The generated hypomorphic Sp4 allele mice were grossly normal and displayed no increased lethality. Unexpectedly, the mutant mice displayed both vacuolization in the hippocampus and abnormal behavioral phenotypes, particularly with regard to contextual memory and sensorimotor gating deficits. Hence, these studies suggest a new molecular pathway involving the Sp4 gene that functions within the hippocampu...

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“…Careful examination of Sp3 nullizygotes indicates that these animals also suffer from defects in skeletal bone ossification and tooth development (6,7). Mice lacking Sp4 appear to develop normally in utero, but two-thirds of newborn animals perish within 4 weeks of birth of undetermined causes (8,9). Surviving Sp4 nullizygotes are growth-retarded, male animals fail to breed despite normal spermatogenesis, and female animals exhibit a delayed onset of puberty.…”

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Sp2 DNA Binding Activity and trans-Activation Are Negatively Regulated in Mammalian Cells

Moorefield

Fry

Horowitz

2004

Journal of Biological Chemistry

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Complex phenotype of mice homozygous for a null mutation in the Sp4 transcription factor gene

Cited by 54 publications

References 26 publications

Neural development is dependent on the function of specificity protein 2 in cell cycle progression

Neural development is dependent on the function of specificity protein 2 in cell cycle progression

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

Sp2 DNA Binding Activity and trans-Activation Are Negatively Regulated in Mammalian Cells

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