KATNAL1 regulation of sertoli cell microtubule dynamics is essential for spermiogenesis and male fertility.

Spermatogenesis is a complex process reliant upon interactions between germ cells (GC) and supporting somatic cells. Testicular Sertoli cells (SC) support GCs during maturation through physical attachment, the provision of nutrients, and protection from immunological attack. This role is facilitated by an active cytoskeleton of parallel microtubule arrays that permit transport of nutrients to GCs, as well as translocation of spermatids through the seminiferous epithelium during maturation.

Collagen dysregulation in the dermis of the Sagg/+ mouse: a loose skin model.

The Sagg/+ mouse is an ethylnitrosourea-derived mutant with a dermal phenotype similar to some of the subtypes of Ehlers-Danlos syndrome (EDS) and cutis laxa. The dermis of the Sagg/+ mouse has less dense and more disorganized collagen fibers compared to controls. The size of extracted Type I dermal collagen was the same as that observed in normal skin; however, more collagen could be extracted from Sagg/+ skin, which also showed decreased collagen content and decreased steady-state levels of alpha1(I), alpha2(I), alpha1(V), and alpha2(V) procollagen mRNAs.

Demonstration of autoimmunity in the tight skin-2 mouse: a model for scleroderma.

The tight skin-2 (Tsk2/+) mouse has been proposed as an animal model of systemic sclerosis (SSc) because this animal exhibits increased collagen synthesis and accumulation in the dermis. The Tsk2/+ mouse also has been reported to have a mononuclear cell infiltrate in the dermis; however, to date no evidence of autoimmunity has been described in this animal model. We report here that Tsk2/+ mice harbor numerous autoantibodies in their plasma including some, which are similar to those, present in SSc patients.

Progressive loss of motor neuron function in wasted mice: effects of a spontaneous null mutation in the gene for the eEF1 A2 translation factor.

Wasted (wst) is a spontaneous autosomal recessive mutation in which the gene encoding translation factor eEF1A2 is deleted. Homozygous mice show tremors and disturbances of gait shortly after weaning, followed by motor neuron degeneration, paralysis, and death by about 28 days. We have now conducted a more detailed analysis of neuromuscular pathology in these animals.

Interactions between imprinting effects in the mouse.

Mice with uniparental partial or complete disomies for any one of 11 identified chromosomes show abnormal phenotypes. The abnormalities, or imprinting effects, can be attributable to an incorrect dosage of maternal or paternal copies of imprinted gene(s) located within the regions involved. Here we show that combinations of partial disomies may result in interactions between imprinting effects that seemingly independently affect fetal and/or placental growth in different ways or modify neonatal and postnatal imprinting effects.

Two ENU-induced mutations in Rasgrf1 and early mouse growth retardation.

When paternally transmitted, two independent ENU-induced mutations showed reduced whole body wet weight soon after birth. The mutations were mapped to Chromosome 9 (Chr 9) between the markers D9Mit208 and D9Mit215. Their map position and imprinted status suggested that they might alter RAS protein-specific guanine nucleotide releasing factor 1 expression.

Transcriptional activation of alpha 1(III) procollagen gene in Tsk2/+ dermal fibroblasts.

Transient transfection experiments into Tsk2/+ and normal dermal fibroblasts were performed using four successively shorter Col3a1 promoter deletion constructs: #103, #110, #114, and #120 fused to the chloramphenicol-acetyl-transferase (CAT) reporter gene. The transcriptional activity in Tsk2/+ and normal dermal fibroblasts driven by the three longer constructs was equal. With the shortest construct, #120 (-96 to +16bp) the transcriptional activity in Tsk2/+ fibroblasts was 25 times higher than in normal fibroblasts.

Novel phenotypes identified by plasma biochemical screening in the mouse.

We used ENU mutagenesis in the mouse for the rapid generation of novel mutant phenotypes for both gene function studies and use as new animal models of human disease (Nolan et al. 2000b). One focus of the program was the development of a blood biochemistry screen.

A new mouse mutant, skijumper.

Low blood sugar levels are a well-known cause of severe illness and often death in newborn humans, especially those that are small for age. Few of the causes of neonatal hypoglycemia are known, and many remain to be found. We describe a novel mouse mutant, skijumper (skimp), in which pups, despite feeding well, have low levels of glucose and develop opisthotonos, followed by death typically within a few days after birth.

Alternative non-coding splice variants of Nespas, an imprinted gene antisense to Nesp in the Gnas imprinting cluster.

The Gnas locus on mouse Chr 2 represents a unique cluster of overlapping imprinted genes. Three of these in the order Nesp--Gnasxl--Gnas are transcribed in the sense direction with Nesp having maternal-specific expression, Gnasxl having paternal expression, and Gnas as being biallelically expressed in most tissues. A fourth imprinted gene, Nespas, is paternally expressed, lies antisense to Nesp, and expresses an unspliced transcript.