Genome-wide analysis of the zebrafish Klf family identifies two genes important for erythroid maturation

Abstract

Krüppel-like transcription factors (Klfs), each of which contains a CACCC-box binding domain, have been investigated in a variety of developmental processes, such as angiogenesis, neurogenesis and somatic-cell reprogramming. However, the function and molecular mechanism by which the Klf family acts during developmental hematopoiesis remain elusive. Here, we report identification of 24 Klf family genes in zebrafish using bioinformatics. Gene expression profiling shows that 6 of these genes are expressed in blood and/or vascular endothelial cells during embryogenesis. Loss of function of 2 factors (klf3 or klf6a) leads to a decreased number of mature erythrocytes. Molecular studies indicate that both Klf3 and Klf6a are essential for erythroid cell differentiation and maturation but that these two proteins function in distinct manners. We find that Klf3 inhibits the expression of ferric-chelate reductase 1b (frrs1b), thereby promoting the maturation of erythroid cells, whereas Klf6a controls the erythroid cell cycle by negatively regulating cdkn1a expression to determine the rate of red blood cell proliferation. Taken together, our study provides a global view of the Klf family members that contribute to hematopoiesis in zebrafish and sheds new light on the function and molecular mechanism by which Klf3 and Klf6a act during erythropoiesis in vertebrates.

Krüpple-like factors 7 and 6a mRNA expression in adult zebrafish central nervous system

“…paraventricular nucleus). A somewhat similar klf6a expression pattern is observed in developing (Thisse et al, 2001; Zhao et al, 2010; Xue et al, 2015) and adult zebrafish CNS (this study). Apparent klf6a expression is mainly found in the hindbrain (dorsal region) and spinal cord of young zebrafish embryos (e.g.…”

“…Similar to Klf7 / klf7 , studies of Klf6 / klf6a or KLF6 distribution in the CNS were conducted only in embryonic zebrafish (Thisse et al, 2001; Xue et al, 2015), developing (Laub et al, 2001b) and adult mice (Jeong et al, 2009), with KLF6 expression in the adult mouse brain limited to the forebrain. In the embryonic and neonatal mouse CNS (E11.5-P1), Klf6 expression became apparent first in the caudal hindbrain (dorsal regions) and neural tube (ventral horn) (Laub et al, 2001b).…”

“…Its mRNA ( Klf7 / klf7 ) is strongly expressed in developing mouse (Laub et al, 2001a) and zebrafish CNS (Thisse and Thisse, 2004; Li et al, 2010; Xue et al, 2015). Klf7 mutant mice exhibit defects in several brain structures including olfactory bulb, cerebral cortex, hippocampus and retinal axons (Laub et al, 2005).…”

“…Klf6 / klf6a mRNA is also expressed in the CNS of embryonic mice and zebrafish, but its expression domains are more limited compared to Klf7 / klf7 (Laub et al, 2001b; Thisse et al, 2001; Xue et al, 2015). There is a wealth of information on KLF6/Klf6a roles in tumor suppression and pathogenesis of several cancers (reviewed by Andreoli et al, 2010; Moore et al, 2011), and erythroid maturation (Xue et al, 2015), but there is little published data on KLF6/Klf6a involvement in neural development and function. Also similar to klf7 , klf6a expression is greatly increased in the regenerating RGCs in adult zebrafish, and Klf6a likely promotes successful optic nerve regeneration (Veldman et al, 2007).…”

RNA sequencing analysis reveals protective role of kruppel-like factor 3 in colorectal cancer

“…KLF1 knock-out mice die of severe anemia secondary to β-globin deficiency about 2 weeks after embryonic formation [13, 14]. KLF2 is expressed in the heart tube and vasculature and is involved in blood vessel remodeling, heart valve development [11, 15], and primitive hematopoiesis [16, 17]. …”