Myocardium defects and ventricular hypoplasia in mice homozygous null for the <i>Forkhead Box m1</i> transcription factor

Ramakrishna, Sneha; Kim, Il-man; Petrovič, Vladimír; Malin, Dmitriy; Wang, I‐Ching; Kalin, Tanya V.; Meliton, Lucille N.; Zhao, You Yang; Ackerson, Timothy; Qin, Yimin; Malik, Asrar B.; Costa, Robert H.; Kalinichenko, Vladimir V.

doi:10.1002/dvdy.21113

Cited by 65 publications

(72 citation statements)

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“…47 Foxm1-/-embryos have approximately 3-fold fewer cardiomyocytes, with defects in DNA replication and mitosis, 48 but no increase in apoptosis was noted. 27,48 Similarly, embryos with KLF1 mutations have fewer blood cells that display aberrant S-phase entry, coincident with reduced Foxm1.…”

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confidence: 94%

“…27,48 Similarly, embryos with KLF1 mutations have fewer blood cells that display aberrant S-phase entry, coincident with reduced Foxm1. Foxm1 mRNA is present in lower amounts in KLF1+/-KLF2-/-than in KLF1-/-KLF2+/-embryonic erythroid cells, suggesting that it is more responsive to KLF2 than KLF1, and correlating with the anemia phenotype in E10.5 KLF1+/-KLF2-/-but not KLF1-/-KLF2+/-whole-mount embryos.…”

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confidence: 99%

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Kruppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation

et al. 2014

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The Krüppel-like transcription factors KLF1 and KLF2 are essential for embryonic erythropoiesis. They can partially compensate for each other during mouse development, and coordinately regulate numerous erythroid genes, including the b-like globins. Simultaneous ablation of KLF1 and KLF2 results in earlier embryonic lethality and severe anemia. In this study, we determine that this anemia is caused by a paucity of blood cells, and exacerbated by diminished b-like globin gene expression. The anemia phenotype is dose-dependent, and, interestingly, can be ameliorated by a single copy of the KLF2, but not the KLF1 gene. The roles of KLF1 and KLF2 in maintaining normal peripheral blood cell numbers and globin mRNA amounts are erythroid cell-specific. Mechanistic studies led to the discovery that KLF2 has an essential function in erythroid precursor maintenance. KLF1 can partially compensate for KLF2 in this role, but is uniquely crucial for erythroid precursor proliferation through its regulation of G1-to S-phase cell cycle transition. A more drastic impairment of primitive erythroid colony formation from embryonic progenitor cells occurs with simultaneous loss of KLF1 and KLF2 than with loss of a single factor. KLF1 and KLF2 coordinately regulate several proliferation-associated genes, including Foxm1. Differential expression of FoxM1, in particular, correlates with the observed KLF1 and KLF2 gene dosage effects on anemia. Furthermore, KLF1 binds to the FoxM1 gene promoter in blood cells. Thus KLF1 and KLF2 coordinately regulate embryonic erythroid precursor maturation through the regulation of multiple homeostasis-associated genes, and KLF2 has a novel and essential role in this process.

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confidence: 94%

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Kruppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation

et al. 2014

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“…Targeted deletion of the Foxm1 gene in mice (Foxm1 Ϫ/Ϫ ) is embryonic lethal due to multiple abnormalities in the development of the lung, liver, heart, and blood vessels (17)(18)(19)(20). FOXM1 inactivation in cycling cells caused delays in DNA replication and mitosis, and altered expression of cell cycle regulatory genes (20)(21)(22)(23). Consistent with an important role of FOXM1 in cell cycle progression, FOXM1 induced proliferation of tumor cells during development of lung, liver, brain, and prostate cancers (21,(24)(25)(26)(27).…”

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FOXM1 Promotes Allergen-Induced Goblet Cell Metaplasia and Pulmonary Inflammation

Ren

Shah

Ustiyan

et al. 2013

Molecular and Cellular Biology

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Chronic airway disorders, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are associated with persistent pulmonary inflammation and goblet cell metaplasia and contribute to significant morbidity and mortality worldwide. While the molecular pathogenesis of these disorders is actively studied, little is known regarding the transcriptional control of goblet cell differentiation and mucus hyperproduction. Herein, we demonstrated that pulmonary allergen sensitization induces expression of FOXM1 transcription factor in airway epithelial and inflammatory cells. Conditional deletion of the Foxm1 gene from either airway epithelium or myeloid inflammatory cells decreased goblet cell metaplasia, reduced lung inflammation, and decreased airway resistance in response to house dust mite allergen (HDM). FOXM1 induced goblet cell metaplasia and Muc5AC expression through the transcriptional activation of Spdef. FOXM1 deletion reduced expression of CCL11, CCL24, and the chemokine receptors CCR2 and CX3CR1, resulting in decreased recruitment of eosinophils and macrophages to the lung. Deletion of FOXM1 from dendritic cells impaired the uptake of HDM antigens and decreased cell surface expression of major histocompatibility complex II (MHC II) and costimulatory molecule CD86, decreasing production of Th2 cytokines by activated T cells. Finally, pharmacological inhibition of FOXM1 by ARF peptide prevented HDM-mediated pulmonary responses. FOXM1 regulates genes critical for allergen-induced lung inflammation and goblet cell metaplasia.

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“…151 Finally, FoxM1 is essential for the proliferation of cardiomyocytes during heart development (see Table). 153 Disruption of FoxM1 results in ventricular hypoplasia, diminished DNA replication, and mitosis in cardiomyocytes during development. …”

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Forkhead Transcription Factors and Cardiovascular Biology

Papanicolaou

Izumiya

Walsh

2008

Circulation Research

108

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Abstract-TheKey Words: angiogenesis Ⅲ endothelial cells Ⅲ forkhead Ⅲ transcription factors Ⅲ vascular biology F orkhead/winged helix proteins are characterized by a conserved 100 -amino acid domain called the "forkhead box." 1 These proteins function as transcription factors, and they participate in diverse biological processes in development and disease. 2,3 The forkhead family in humans consists of 39 distinct members, which have been divided into 19 subgroups (Forkhead box [FOX] A to S). The FoxO subgroup of transcription factors has received the most attention because of their recently discovered roles in controlling detoxification of reactive oxygen species (ROS), 5,6 cell cycle, 7 apoptosis, 8,9 DNA repair, 7 glucose metabolism, 10 -14 and the regulation of cell size. 15-17a Thus, this review will primarily focus on the FoxO subgroup in cardiovascular cells. The reader should note that the role of forkhead factors in endothelial cells and angiogenesis has been reviewed recently. 17b FoxO OverviewThe forkhead transcription factors of the O subgroup (FoxO) consist of 4 members, FoxO1 (FKHR), FoxO3 (FKHRL1), FoxO4 (AFX), and FoxO6. FoxO1, FoxO3, and FoxO4 are expressed in most tissues to varying degrees, 18,19 FoxO1 is abundantly expressed in adipose tissues, FoxO3 is abundant in cardiac and neuronal tissues, and FoxO4 is abundant in skeletal and cardiac muscle. FoxO6 is predominantly expressed in a specific region of the brain. 20 Interest in the FoxO subfamily developed when it was reported that alveolar rhabdomyosarcomas resulted from a genetic translocation forming a fusion gene composed of sequences from the "paired box" (Pax) and "forkhead in rhabdomyosarcoma" (FKHR) transcription factors. 21 The fusion protein contained an intact DNA binding domain from Pax3 and part of the DNA binding and C-terminal domains of FKHR (later to be termed FoxO1 1 ). In further studies, another forkhead related factor termed AFX1, because of its location on the X chromosome (later to be termed FoxO4), was shown to participate in translocations that resulted in human malignancies involving fusion with the myeloid-lymphoid leukemia (MLL) gene. 22 Further cloning studies based on sequence similarities to FKHR resulted in the isolation of the gene FKHRL1, 23 later to be termed FoxO3. In more recent studies, the FoxO6 gene has been assigned to the FoxO group because it displays sequence similarity to the other members, although its regulatory properties have diverged from those of the other Original received September 13, 2007; revision received November 13, 2007; accepted November 15, 2007 FoxO factors. 24 For the purposes of this review, the generic term FoxO is used to describe properties identified in one or more of FoxO1, FoxO3, and FoxO4, unless otherwise specified. The functional diversification of the different FoxO isoforms was revealed by targeted gene disruption in mice (Table). FoxO1-null embryos die on embryonic day 10.5 as a consequence of incomplete vascular development. 25,26 FoxO3-null mice survive to adulth...

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Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box m1 transcription factor

Cited by 65 publications

References 60 publications

Kruppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation

Kruppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation

FOXM1 Promotes Allergen-Induced Goblet Cell Metaplasia and Pulmonary Inflammation

Forkhead Transcription Factors and Cardiovascular Biology

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