Potassium Channel-Associated Bioelectricity of the Dermomyotome Determines Fin Patterning in Zebrafish.

The roles of bioelectric signaling in developmental patterning remain largely unknown, although recent work has implicated bioelectric signals in cellular processes such as proliferation and migration. Here, we report a mutation in the inwardly rectifying potassium channel (kir) gene, kcnj13/kir7.1, that causes elongation of the fins in the zebrafish insertional mutant Dhi2059. A viral DNA insertion into the noncoding region of kcnj13 results in transient activation and ectopic expression of kcnj13 in the somite and dermomyotome, from which the fin ray progenitors originate. We made an allele-specific loss-of-function kcnj13 mutant by CRISPR (clustered regularly interspaced short palindromic repeats) and showed that it could reverse the long-finned phenotype, but only when located on the same chromosome as the Dhi2059 viral insertion. Also, we showed that ectopic expression of kcnj13 in the dermomyotome of transgenic zebrafish produces phenocopies of the Dhi2059 mutant in a gene dosage-sensitive manner. Finally, to determine whether this developmental function is specific to kcnj13, we ectopically expressed three additional potassium channel genes: kcnj1b, kcnj10a, and kcnk9 We found that all induce the long-finned phenotype, indicating that this function is conserved among potassium channel genes. Taken together, our results suggest that dermomyotome bioelectricity is a new fin-patterning mechanism, and we propose a two-stage bioelectricity model for zebrafish fin patterning. This ion channel-regulated bioelectric developmental patterning mechanism may provide with us new insight into vertebrate morphological evolution and human congenital malformations.

KANK1 inhibits cell growth by inducing apoptosis through regulating CXXC5 in human malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of rare sarcomas with a poor prognosis due to its highly invasive nature and limited treatment options. Currently there is no targeted-cancer therapy for this type of malignancy. Thus, it is important to identify more cancer driver genes that may serve as targets of cancer therapy. Through comparative oncogenomics, we have found that KANK1 was a candidate tumor suppressor gene (TSG) for human MPNSTs. Although KANK1 is known as a cytoskeleton regulator, its tumorigenic function in MPNSTs remains largely unknown. In this study, we report that restoration of KANK1 in human MPNST cells inhibits cell growth both in human cell culture and xenograft mice by increasing apoptosis. Consistently, knockdown of KANK1 in neurofibroma cells promoted cell growth. Using RNA-seq analysis, we identified CXXC5 and other apoptosis-related genes, and demonstrated that CXXC5 is regulated by KANK1. Knockdown of CXXC5 was found to diminish KANK1-induced apoptosis in MPNST cells. Thus, KANK1 inhibits MPNST cell growth though CXXC5 mediated apoptosis. Our results suggest that KANK1 may function as a tumor suppressor in human MPNSTs, and thus it may be useful for targeted therapy.