Fibronectin type III domain-containing 3 (Fndc3) genes encode a novel family of cytosolic tail-anchored proteins found in metazoa, including humans and mice. Male mice lacking Fndc3a are sterile due to opening of spermatid intercellular bridges and loss of adhesion between spermatids and Sertoli cells. In the mouse testis, Fndc3a and Fndc3b are transcribed primarily in germ cells, with highest levels of Fndc3a transcripts in spermatocytes and Fndc3b transcripts in elongating spermatids. Analysis of mice with germ cell specific knockout of Fndc3a or Fndc3b revealed that Fndc3a, but not Fndc3b, is required in a germ cell-intrinsic manner for male fertility. Loss of Fndc3a in adult mice demonstrated that Fndc3a is also required for maintenance of adult spermatogenesis. Although lipids accumulate in Leydig cells in mice lacking Fndc3a in all tissues, Fndc3a is not required in Leydig cells for fertility. Possible mechanisms for loss of spermatid-Sertoli cell adhesion and intercellular bridge formation and maintenance in Fndc3a mutant mice were investigated. Defects in androgen signaling were not detected in sterile male Fndc3a mutant mice, indicating loss of spermatid-Sertoli cell adhesion was not due to loss of androgen signaling. Moreover, the testis of Fndc3a mutants displayed no defect in either the synthesis of ultra long chain polyunsaturated fatty acids (ULC-PUFA's), or the expression and formation of TEX14 rings required for maintenance of intercellular bridges, suggesting that failure in intercellular bridges is due to a novel defect. To begin to investigate how FNDC3A functions in spermatogenesis, interacting proteins were identified. FNBP4, SMURF1, and IQGAP1 were identified as WW-domain containing proteins involved in actin dynamics that can interact with FNDC3A and are co-expressed with Fndc3a in developing germ cells. Surprisingly, these interactions occur independently of conserved WW-domain binding motifs in FNDC3A. Instead, a novel conserved "KKLK sequence" within FNDC3 proteins was identified that is required for interaction. These results raise the possibility that loss of Fndc3a in spermatids leads to abnormal actin regulation resulting in opening of intercellular bridges and loss of spermatid-Sertoli adhesion. Models are presented for how FNDC3A may function in regulating the spermatid actin cytoskeleton for male fertility.
Mouse strain background can influence vulnerability to excitotoxic neuronal cell death and potentially modulate phenotypes in transgenic mouse models of human disease. Evidence supports a contribution of excitotoxicity to the selective death of medium spiny neurons in Huntington's disease (HD). Here, we assess whether strain differences in excitotoxic vulnerability influence striatal cell death in a knock-in mouse model of HD. Previous studies that evaluated resistance to excitotoxic lesions in several mouse models of HD had variable outcomes. In the present study, we directly compare one model on two different background strains to test the contribution of strain to excitotoxicity-mediated neurodegeneration. Mice of the FVB/N strain, which are highly vulnerable to excitotoxicity, become extremely resistant to quinolinic acid-induced striatal neurodegeneration with age, when carrying a huntingtin (Htt) allele expressing a HD transgene (CAG140). The resistance is much greater than the age-dependent resistance that has been previously reported in YAC128 mice. By 12 months of age, both heterozygous and homozygous FVB.CAG140 mice displayed virtually complete resistance to quinolinic acid-induced striatal neurodegeneration. A similar resistance develops in CAG140 mice on a C57BL/6N background although the effect size is smaller because C57BL/6N mice are already resistant due to genetic background. In a direct comparison with the YAC128 mice, FVB.CAG140 mice have greater resistance. FVB.CAG140 mice are also resistant to neurodegeneration following kainic acid-induced status epilepticus suggesting the existence of a common cellular mechanism that provides protection against multiple types of excitotoxic insult. These findings establish FVB.CAG140 mice as a useful model to investigate the cellular and molecular mechanisms that confer neuroprotection against excitotoxicity.
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