Genetic compensation represents one of the important ways in which organisms maintain their genetic robustness in spite of adverse perturbations. Loss of a protein function can be substituted by upregulation of other ancestrally-related genes, leading to transcriptional adaptation. Although the exact molecular mechanism underlying genetic compensation has not been fully elucidated, recent reports suggest the possible role of Premature Stop Codons (PTCs) and Nonsense-mediated mRNA decay (NMD) in enhancing the transcription of compensatory genes. Such altered gene expression has been proposed to help explain the phenotypic differences between knock-down and knock-out animal models. Here I present new data that characterize possible compensation of two-pore channel type 2 (TPC2) by NMD-sti...[ Read more ]

Genetic compensation represents one of the important ways in which organisms maintain their genetic robustness in spite of adverse perturbations. Loss of a protein function can be substituted by upregulation of other ancestrally-related genes, leading to transcriptional adaptation. Although the exact molecular mechanism underlying genetic compensation has not been fully elucidated, recent reports suggest the possible role of Premature Stop Codons (PTCs) and Nonsense-mediated mRNA decay (NMD) in enhancing the transcription of compensatory genes. Such altered gene expression has been proposed to help explain the phenotypic differences between knock-down and knock-out animal models. Here I present new data that characterize possible compensation of two-pore channel type 2 (TPC2) by NMD-stimulated upregulation of the gene coding for its paralogue, two-pore channel type 1 (TPC1). Furthermore, I show that this compensation occurs in TPC2 mutant embryos, but not when they are injected with a TPC1-morpholino, and that the upregulation of TPC1 in the TPC2 mutant maintains the generation of myogenic Ca²⁺ signals required for myofibrillogenesis during early slow muscle cell (SMC) differentiation.

Membrane impermeable nicotinic acid adenine dinucleotide phosphate (NAADP) has been described as one of the most potent intracellular Ca²⁺ mobilizing messengers, and it has been reported to induce localized Ca²⁺ release from intracellular acidic Ca²⁺ stores such as lysosomes. TPCs have been proposed as a possible target of NAADP, and TPC2-mediated Ca²⁺ release has been reported to be necessary for normal myofibrillogenesis in the trunk of zebrafish embryos. Due to current controversies regarding the identity of the endogenous agonist of TPCs in specific cell types, I attempted to stimulate a Ca²⁺ response in primary cultures of zebrafish SMCs by applying exogenous, membrane permeable NAADP-acetoxymethyl ester (NAADP-AM). I was, however, unable to achieve this. Control experiments suggested that this failure was due to the instability of the NAADP-AM rather than a problem with the experimental protocol applied.