Acta2-CatCh-IRES-lacZ transgenic mice express the calcium-translocating channelrhodopsin CatCh and lacZ under control of the Acta2 locus promoter/enhancer regions within the BAC transgene. Acta2-CatCh-IRES-lacZ mice from founder line B8-3 exhibit robust expression levels of CatCh and lacZ in smooth muscle cells (e.g., blood vessels, lung airways, bladder and gut) - consistent with endogenous Acta2. Additional details described further below. CatCh is a calcium-translocating channelrhodopsin variant designed to have enhanced Ca2+ permeability, accelerated response kinetics and ~70-fold greater sensitivity to blue-to-green light (~450-530 nm; max 474 nm). Additional CatCh information is described below. For Acta2-CatCh-IRES-lacZ transgenic mice, illumination of the CatCh molecule with this light in smooth muscle results in reversible photostimulation of channel opening, calcium inflow and contraction of the muscle. The donating investigator reports that expression patterns appear to mimic the endogenous Acta2 expression. Specifically, lacZ staining was observed in blood vessels (heart, lung, diaphragm and brain), small intestine and bladder. CatCh activation with light was observed in blood vessels (cremaster and femoral vessels). They have not tested expression in other smooth muscle-containing tissues to date (February 2019). Before exposure to the specific wavelength of activating light, lacZ expression is observable, and the CatCh imparts no muscle cell depolarization and no muscle contraction. Upon exposure to ~473 nm light, CatCh activation causing channel opening, calcium inflow and muscle contraction. Subsequent removal of the activating light returns muscle to the baseline state (allowing relaxation). Mice hemizygous for the Acta2-CatCh-IRES-lacZ transgene (now backcrossed onto C57BL/6J more than nine generations [February 2019]) are viable and fertile with normal breeding, and no reported gross phenotypic abnormalities. The donating investigator reports that hemizygous Acta2-CatCh-IRES-lacZ mice had some incidence of lethality (gastrointestinal hemorrhage, pale organs) when first created, but subsequent backcrossing to C57BL/6J eliminated this lethality. As a precaution, the donating investigator does not recommend making this strain homozygous. Of note, another mouse line created using the same BAC exhibited some incidence of lethality (Stock No. <a href="https://www.jax.org/strain/025406">025406</a>). The bacterial opsins are retinal-binding proteins that combine a light-sensitive domain with an ion channel or pump; providing light-dependent ion transport, membrane potential alteration, and sensory functions to bacteria. Chlamydomonas reinhardtii-derived channelrhodopsin-2 (ChR2 or cop4) is a blue light-driven cation channel that depolarizes the cell and causes action potentials. The calcium translocating channelrhodopsin (CatCh) is a ChR2 variant modified to have an L132C amino acid substitution for enhanced Ca2+ permeability; resulting in accelerated response time and a voltage response that is ~70-fold more light sensitive than wildtype ChR2. As such, illuminating CatCh-expressing cells with blue-to-green light (~450-530 nm; max 474 nm) leads to rapid and reversible photostimulation of channel opening (e.g, calcium inflow and contraction of muscle, or robust action potential firing activity in neurons, etc.). Because CatCh activation is possible at naturally occurring light intensities while maintaining high temporal precision, it may also have applications in gene-therapeutic visual restoration efforts. This mouse model is available by way of a collaborative effort between Cornell/National Heart Lung Blood Resource for Optogenetic Mouse Signaling (<a href="http://chromus.vet.cornell.edu">CHROMus</a>) and The Jackson Laboratory.

Acta2-CatCh-IRES-lacZ transgenic mice express the calcium-translocating channelrhodopsin CatCh (an L132C mutant channelrhodopsin with enhanced Ca2+ permeability, accelerated response kinetics and ~70-fold greater light sensitivity) in smooth muscle cells (e.g., blood vessels, lung airways, bladder and gut). Illumination of the CatCh molecule with blue-to-green light in smooth muscle results in reversible photostimulation of channel opening, calcium inflow and contraction of the muscle.

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