Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in the Cacna1f gene, encoding the α 1F subunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in the nob2 ( no b-wave 2 ) mouse, a naturally occurring mutant caused by a null mutation in Cacna1f . Not surprisingly, the b -waves of both the light- and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the presynaptic marker Ribeye, indicating potential points of ectopic synapse formation. However, the morphology of the presynaptic Ribeye-positive profiles is abnormal. While cone pedicles are present their morphology also appears compromised. Characterizations of visual responses in retinal ganglion cells in vivo , under photopic conditions, demonstrate that ON-center cells have a reduced dynamic range, although their basic center-surround organization is retained; no alteration in the responses of OFF-center cells was evident. These results indicate that nob2 mice are a valuable model in which to explore the pathophysiological mechanisms associated with Cacna1f mutations causing CSNB2, and the subsequent effects on visual information processing. Further, the nob2 mouse represents a model system in which to define the signals that guide synapse formation and/or maintenance in the OPL.

At the turn of the millennium, we are poised to amass more knowledge than ever before about the influence of gene function on living systems, due to rapid advances in technology. The author underscores the importance of animal models-particularly mice-as our knowledge of gene sequences grows, and explains why animals will continue to be crucial to biomedical research as we advance our understanding of complex diseases, behavior, and whole systems.

The harlequin ichthyosis (ichq) mouse mutation arose spontaneously in 1989 in a colony of BALB/cJ mice at The Jackson Laboratory. Affected mice developed thick skin due to formation of compact, orthokeratotic scales that fractured over articular surfaces, secondary to bending. Harlequin ichthyosis mice on the inbred BALB/cJ background died between 9 and 12 days of age. Onset of the clinical phenotype corresponded with emergence of hair fibers from follicles at 5 days of age. There was marked proliferation of the root sheaths of anagen hair follicles, limited to the region within the dermis. Sebaceous glands were present but small compared with those of littermate controls. Emerging hair fibers were surrounded by a thick, compact sheath of cornified cells. Mutant skin contained large mitochondria with lamellar-shaped, electron-dense structures at the ultrastructural level. Keratohyalin granules were smaller and less pleomorphic than those in control mice. Lamellar bodies were not evident in either mutant or littermate control mice. Using a panel of antibodies to evaluate changes in keratinocyte differentiation, mouse-specific keratin 6 was overexpressed in the suprabasilar, hyperplastic epidermis. Loricrin expression, within the cytoplasm of cells in the stratum granulosum, decreased rapidly postmortem, unlike that in normal mice where it was stable for over 24 hours postmortem. Filaggrin expression, within granules of cells in the stratum granulosum, was prominent, corresponding to hypergranulosis evident by light microscopy in mutant mouse skin. Skin grafts from harlequin ichthyosis mice grafted onto immunodeficient nude mice maintained the phenotype for the 10-week observation period. The mutant gene locus mapped to the proximal end of mouse chromosome 19 and is inherited as a fully penetrant autosomal recessive gene. The harlequin ichthyosis mouse mutation is very similar to human type 2 harlequin ichthyosis for which it may be a good model.