Essential Role of the Zinc Finger Transcription Factor Casz1 for Mammalian Cardiac Morphogenesis and Development

Liu, Zhihui; Li, Wenling; Ma, Xuefei; Ding, Nancy; Spallotta, Francesco; Southon, Eileen; Tessarollo, Lino; Gaetano, Carlo; Mukouyama, Yoh‐suke; Thiele, Carol J.

doi:10.1074/jbc.m114.570416

Cited by 67 publications

(65 citation statements)

References 61 publications

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“…Casz1 SALacZ is predicted to be a null allele by causing premature transcription arrest before the zinc finger domains (Figure 2A). Accordingly, no viable Casz1 SALacZ/SALacZ homozygotes were found in E10.5 litters (wild-type: 10/33; Casz1 SALacZ/+ : 21/33; Casz1 SALacZ/SALacZ : 0/33) or after birth (n = 0/115), consistent with the previously reported essential role for Casz1 in heart and vascular system development (Charpentier et al, 2013; Christine and Conlon, 2008; Liu et al, 2014). Taking advantage of the Casz1 SALacZ/+ allele, we studied the general expression pattern of the Casz1 locus in developing embryos.…”

Section: Resultssupporting

confidence: 90%

A Conserved Regulatory Logic Controls Temporal Identity in Mouse Neural Progenitors

Mattar

Ericson

Blackshaw

et al. 2015

Neuron

145

166

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SUMMARY Neural progenitors alter their output over time to generate different types of neurons and glia in specific chronological sequences, but this process remains poorly understood in vertebrates. Here we show that Casz1, the vertebrate ortholog of the Drosophila temporal identity factor castor, controls the production of mid-/late-born neurons in the murine retina. Casz1 is expressed from mid/late stages in retinal progenitor cells (RPCs), and conditional deletion of Casz1 increases production of early-born retinal neurons at the expense of later-born fates, whereas precocious misexpression of Casz1 has the opposite effect. In both cases, cell proliferation is unaffected, indicating that Casz1 does not control the timing of cell birth but instead biases RPC output directly. Just as Drosophila castor lies downstream of the early temporal identity factor hunchback, we find that the hunchback ortholog Ikzf1 represses Casz1. These results uncover a conserved strategy regulating temporal identity transitions from flies to mammals.

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Section: Resultssupporting

confidence: 90%

A Conserved Regulatory Logic Controls Temporal Identity in Mouse Neural Progenitors

Mattar

Ericson

Blackshaw

et al. 2015

Neuron

145

166

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“…We note that these findings differ from those reported for a Casz1 gene trap line of mice that were generated from an ESC line carrying a βgeo cassette integrated into the ninth intron of Casz1 (Liu et al, 2014). Mice homozygous for the insertion exhibited embryonic arrest at E16.5, a time point in development much later than those reported here for mice in which Casz1 was depleted in both the primary and secondary heart fields (Casz1 ).…”

Section: Discussioncontrasting

confidence: 55%

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development

Dorr

Amin

et al. 2015

Development

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Organ growth occurs through the integration of external growth signals during the G1 phase of the cell cycle to initiate DNA replication. Although numerous growth factor signals have been shown to be required for the proliferation of cardiomyocytes, genetic studies have only identified a very limited number of transcription factors that act to regulate the entry of cardiomyocytes into S phase. Here, we report that the cardiac para-zinc-finger protein CASZ1 is expressed in murine cardiomyocytes. Genetic fate mapping with an inducible Casz1 allele demonstrates that CASZ1-expressing cells give rise to cardiomyocytes in the first and second heart fields. We show through the generation of a cardiac conditional null mutation that Casz1 is essential for the proliferation of cardiomyocytes in both heart fields and that loss of Casz1 leads to a decrease in cardiomyocyte cell number. We further report that the loss of Casz1 leads to a prolonged or arrested S phase, a decrease in DNA synthesis, an increase in phospho-RB and a concomitant decrease in the cardiac mitotic index. Taken together, these studies establish a role for CASZ1 in mammalian cardiomyocyte cell cycle progression in both the first and second heart fields.

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“…6C), (3) CASZ1bΔ168/ CASZ1bΔ186 subcellular localization study (Fig. 1C), and (4) CASZ1bΔ168 subcellular study with or without CRM1 inhibitor treatment (Fig. 7), we demonstrate that there is a NES signal within AA168–192 in the CASZ1 protein.…”

Section: Discussionmentioning

confidence: 57%

“…Representative images are shown in Fig. 9B for the four scoring categories of CASZ1 immunoreactivity detected in the TMA: (1) Score 0: negative, no reactivity to <1% positive nuclei; (2) score 1: 1–10% positive nuclei; (3) score 2: 10–50% positive nuclei; (4) score 3: strong positive, greater than 50% positive nuclei, respectively. Using 10% positive nuclear staining as a cut off, Chi-square analysis showed that the samples scoring 0 and 1 with low nuclear CASZ1 expression are associated with MYCN amplification, unfavorable Shimada histology and high risk (Table 1, all p<0.05; chromosome 1p status not available for this archival case series).…”

Section: Resultsmentioning

confidence: 99%

“…For indirect immunofluorescent cell staining, an anti-FLAG M2 monoclonal antibody (Sigma, catalog: #F1804) and an Alexa Fluor 594-conjugated goat anti-mouse antibody (ThermoFisher Scientific, catalog: #A-11005) were used to detect FLAG-CASZ1b. Adult mouse eye sections and mouse xenograft tumors of human NB cell line that has been stably transfected with tetracycline inducible CASZ1 (NGPtetCASZ1) were dissected and stained as following the previously described protocol (4). A rabbit anti-CASZ1 antibody (1:1000) (made in collaboration with Rockland antibodies & assays) was used to detect CASZ1 protein.…”

Section: Methodsmentioning

confidence: 99%

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Identification of CASZ1 NES reveals potential mechanisms for loss of CASZ1 tumor suppressor activity in neuroblastoma

et al. 2016

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As a transcription factor, localization to the nucleus and the recruitment of co-factors to regulate gene transcription is essential. Nuclear localization and nucleosome remodeling and histone deacetylase (NuRD) complex binding are required for the zinc finger transcription factor CASZ1 to function as neuroblastoma (NB) tumor suppressor. However, the critical amino acids (AAs) that are required for CASZ1 interaction with NuRD complex and the regulation of CASZ1 subcellular localization have not been characterized. Through alanine scanning, immunofluorescence cell staining and co-immunoprecipitation we define a critical region at the CASZ1 N-terminus (AA23-40) that mediates the CASZ1b nuclear localization and NuRD interaction. Furthermore, we identify a nuclear export signal (NES) at the N-terminus (AA176-192) that contributes to CASZ1 nuclear-cytoplasmic shuttling in a chromosomal maintenance 1 (CRM1)-dependent manner. An analysis of CASZ1 protein expression in a primary neuroblastoma tissue microarray shows that high nuclear CASZ1 staining is detected in tumors from NB patients with good prognoses. In contrast, cytoplasmic-restricted CASZ1 staining or low nuclear CASZ1 staining is found in tumors from patients with poor prognoses. These findings provide insight into mechanisms by which CASZ1 regulates transcription, and suggests that regulation of CASZ1 subcellular localization may impact its function in normal development and pathologic conditions such as neuroblastoma tumorigenesis.

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Essential Role of the Zinc Finger Transcription Factor Casz1 for Mammalian Cardiac Morphogenesis and Development

Cited by 67 publications

References 61 publications

A Conserved Regulatory Logic Controls Temporal Identity in Mouse Neural Progenitors

A Conserved Regulatory Logic Controls Temporal Identity in Mouse Neural Progenitors

Casz1 is required for cardiomyocyte G1-to-S phase progression during mammalian cardiac development

Identification of CASZ1 NES reveals potential mechanisms for loss of CASZ1 tumor suppressor activity in neuroblastoma

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