KLF7 has been proposed to be a possible candidate gene for phenotypes associated with 2q33.3-q34 deletions, incuding autism spectrum disorder/autistic features (Courtens et al., 1997; Pescucci et al., 2003; Bisgaard et al., 2006; Brandau et al., 2008; Rosenfeld et al., 2010; Jang et al., 2015). Powis et al., 2017 reported 4 unrelated individuals with de novo and potentially damaging missense variants in the KLF7 gene who shared similar clinical features, including developmental delay/intellectual disability, hypotonia, feeding/swallowing issues, psychiatric features, and neuromuscular symptoms; one of these individuals was also diagnosed with autism spectrum disorder. Additional rare de novo non-coding variants in this gene have been observed in ASD probands (Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017). Tian et al., 2022 reported that klf7 +/- mice exhibited a number of ASD-related behaviors, including deficits in social interaction and repetitive behavior.
Molecular Function
The protein encoded by this gene is a member of the Kruppel-like transcriptional regulator family. Members in this family regulate cell proliferation, differentiation and survival and contain three C2H2 zinc fingers at the C-terminus that mediate binding to GC-rich sites. This protein may contribute to the progression of type 2 diabetes by inhibiting insulin expression and secretion in pancreatic beta-cells and by deregulating adipocytokine secretion in adipocytes. This protein also plays a critical role in neuronal morphogenesis and the survival of sensory neurons.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo variants in KLF7 are a potential novel cause of developmental delay/intellectual disability
Klf7 mutant mice displayed abnormal growth, deficits in social interaction, learning and memory, and increased repetitive behavior, but normal olfaction. 631 ASD risk genes are differentially expressed in Klf7 mutant mice. Specifically, Klf7 homozygous mutant mice displayed high mortality of 90% within the first two months, and had severely hypoplastic olfactory bulbs and smaller brains after birth. Mice restored with adeno-associated virus (AAV)-mediated overexpression of Klf7 exhibit restored social interaction and self-grooming behaviors.
References
Type
Title
Author, Year
Primary
Krüppel-like Transcription Factor 7 Is a Causal Gene in Autism Development
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Klf7 conditional ready mice were generated using CRISPR/Cas9 nuclease technology to add loxP sites flanking exon 2. Conditional knockouts were generated by crossing conditional ready mice to mice carrying a Nestin-Cre transgene, resulting in the deletion of exon 2 in neurons, which express Nestin. Mice were kept in a C57BL/6J background.
Allele Type: conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Cyagen Biosciences Inc.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Klf7 conditional ready mice were generated using CRISPR/Cas9 nuclease technology to add loxP sites flanking exon 2. Conditional knockouts were generated by crossing conditional ready mice to mice carrying a Nestin-Cre transgene, resulting in the deletion of exon 2 in neurons, which express Nestin. Mice were kept in a C57BL/6J background.
Allele Type: conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Cyagen Biosciences Inc.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A floxed allele of Klf7 was generated by inserting loxP sites on either side of exon 2. Homozygous Klf7 flox/flox mice (MGI:7328579) were then crossed with Emx1-Cre (2684610) mice to generate Klf7flox/+; Emx1-Cre mice, which were further crossed with Klf7flox/flox mice to generate cKO mice.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Cyagen; Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
IUE was performed with an shRNA targeting KLF7 (shRNA-KLF7) at E14.5. To generate the expression of short hairpin RNAs (shRNAs), two pairs of synthetic oligonucleotides were individually cloned into the pSuper vector (Addgene), in which the shRNAs are under the control of a human H1 promoter.
Allele Type: Knockdown
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Klf7 heterozygous mutant mice exhibited hyperactivity in the open field test, traveled longer distances, and traveled faster compared to WT mice
Description: Klf7 heterozygous mutant mice first developed seizures at 4 months of age and peaked around 1 year old when they were slightly hit or squeezed.
Description: Klf7 heterozygous mutant mice spent less time in the target region, and crossed the platform region less frequently compared to WT controls
Exp Paradigm: Probe test
Description: Klf7 heterozygous mutant mice showed a decreased ability to learn on the fifth day, and had more difficulty locating the platform compared to WT controls
Description: A significant decrease in klf7 expression was confirmed in Nestin-Cre conditional knockout mice
Exp Paradigm: Quantitative PCR (qRT-PCR) and Western blot
Description: ASD risk genes are dysregulated in Klf7 heterozygous mutant mice; Of the 228 total Klf7 targeted ASD genes, 43 showed significantly changed expression
Description: Klf7 homozygous mutant mice exhibited hyperactivity in the open field test, traveled longer distances, and traveled faster compared to WT mice; Klf7 homozygous mutant mice also exhibited a decreased total resting time
Description: Klf7 homozygous mutant mice exhibited severely hypoplastic olfactory bulbs after birth; olfactory bulbs of Klf7 homozygous mutant mice were shorter and smaller than those in WT mice
Description: More than 90% of Klf7 homozygous mutant mice died during the first two months after birth; Klf7 homozygous mutant mice were found to have little or no milk in the stomachs
Description: Klf7 homozygous mutant mice show a decreased number of entries into the food-containing chamber during habituation and test phases compared to WT
Description: Klf7 homozygous mutant mice showed a significantly decreased interaction time ratio and a slightly decreased interaction frequency ratio
Exp Paradigm: interaction time ratio
Description: Klf7 homozygous mutant mice spent less time in the target region, and crossed the platform region less frequently compared to WT controls
Exp Paradigm: Probe test
Description: Klf7 homozygous mutant mice showed obvious learning impairment during the five training periods, and were not able to distinguish the target region at all; Klf7 homozygous mutant mice also had difficulty locating the platform compared to WT controls
Description: A significant decrease in klf7 expression was confirmed in Nestin-Cre conditional knockout mice
Exp Paradigm: Quantitative PCR (qRT-PCR) and Western blot
Description: Klf7 mutant mice displayed fewer Satb2+/Brn2+ cells in layer II and fewer Ctip2+ cells in layer V compared to controls.
Exp Paradigm: layers II, V
Description: Klf7 mutant mice exhibited disorganized polarity in most of the EYFP-expressing cells in the cortical plate compared to controls.
Exp Paradigm: in utero electroporation (IUE) with pCAG-EYFP plasmid
Description: Klf7 mutant mice exhibited a significant decrease in the percentage of EdU+/EYFP+ cells among all EYFP+ cells in the cortical plate compared to controls. Additionally, the proportion of EdU+/Brn2+ cells among all EdU+ cells in the cortical plate was significantly reduced compared to controls.
Exp Paradigm: in utero electroporation (IUE
Description: Klf7 mutant mice exhibited a significantly reduced percentage of EYFP+ cells in the upper layer of the cortex compared to controls, with 30% and 78%, respectively.
Exp Paradigm: in utero electroporation (IUE) with pCAG-EYFP plasmid
Description: Mutant mice exhibited a severe agenesis of the corpus callosum. The fibers of the corpus callosum did not cross the midline, and the anterior commissure was disrupted.
Exp Paradigm: Nissl staining; corpus callosum
Description: Klf7 mutant mice displayed fewer Satb2+/ Brn2+ cells in layer II and Satb2+ cells in layers IIâ??IV compared to controls. Additionally, expression of Ctip2 and Tbr1 were dramatically reduced in the neocortex.
Exp Paradigm: layers IIâ??IV
Description: Mutant mice exhibited significantly fewer EYFP-expressing cells that had migrated into the cortical plate compared to controls.
Exp Paradigm: in utero electroporation (IUE) with EYFP
Description: Klf7 mutant mice exhibited a decrease in the number of cells positive for Tbr2, a marker of intermediate progenitor cells.
Exp Paradigm: Tbr2, marker of intermediate progenitor cells
Description: Klf7 mutant mice exhibited a significant decrease in the proportion of EYFP+/Brn2+ cells among EYFP+ cells in the cortical plate compared to controls.
Exp Paradigm: in utero electroporation (IUE) with EYFP
Description: Mutant mice exhibited significantly decreased expression of GFAP, a marker of astrocytes, in the indusium griseum glia (IGG) E17.5 and P1 and the glial wedge (GW) at E17.5. At P7, mutant mice exhibited no change in glial fate differentiation based on the number of cells positive for GFAP and S100β.
Exp Paradigm: GFAP and S100β, markers of astrocytes
Description: Pioneer axons that express NF200 were observed in WT mice at E15.5, but the number of NF200+ axons near the midline was significantly reduced in mutant mice compared to controls. Additionally, the number of axons expressing the neural cell adhesion molecule L1, another marker for axonal outgrowth, was significantly reduced in mutant mice compared to controls. At E17.5 and P1, mutant mice exhibited a failure of NF200+ axons to pass through the midline, while controls displayed more orderly pathfinding.
Exp Paradigm: NF200 and L1, marker of axons
Description: Mutant mice exhibited a significant migration defect among GFP-expressing cells within the cerebral cortex compared to controls.
Exp Paradigm: cortex
Description: Klf7 mutant mice exhibited a decrease in the percentage of Tbr1+ cells relative to the total number of cells in layer VI compared to controls.
Exp Paradigm: layer VI
Description: Mutant mice exhibited a significant increase in cells with multipolar processes in the inner portion of the intermediate zone compared to controls.
Exp Paradigm: in utero electroporation (IUE) with EYFP
Description: Klf7 mutant mice exhibited a failure of the EYFP+ axon bundles to cross the midline, with most terminating close to the lateral ventricle of the ipsilateral hemisphere. In controls, bundles elongated tangentially along the corpus callosum to the contralateral hemisphere.
Exp Paradigm: in utero electroporation (IUE)
Description: Mutant mice exhibited a significant increase in the number of EYFP-expressing cells in the intermediate zone/subventricular zone/ventricular zone compared to controls.
Exp Paradigm: in utero electroporation (IUE) with EYFP
Description: Klf7 mutant mice exhibited 398 differentially expressed genes, including 103 downregulated genes and 295 upregulated genes, compared to controls. Additionally, gene ontology analysis revealed that enriched terms associated with the downregulated genes were related to cell adhesion and projection during brain development, and that enriched terms associated with the upregulated genes were related to neural development and neurogenesis.
Exp Paradigm: cortex
Description: Klf7 mutant mice exhibited significantly reduced levels of cyclin-dependent kinase inhibitor 1a, a known downstream target of KLF7 involved in neural cytoskeletal remodeling. Additionally, among the downregulated genes related to neuronal migration, one of the most significantly dysregulated genes was rac3, a key regulator of the actin cytoskeleton.
Description: The sagittal brain of mutant mice showed significantly decreased expression of Klf7 in the cortex but similar in the cerebellum compared to controls.
Exp Paradigm: cortex
Description: Mutant mice exhibited a 19% decrease in the number of GFP-expressing cells in the cortical plate, a 12% increase in cells in the intermediate zone, and a 7% increase in cells in the subventricular zone/ventricular zone. Additionally, mutant mice exhibited a loss of proper radial migration of a subset of the neuronal cells in the cortex.
Exp Paradigm: in utero electroporation (IUE)
