We show that the paralogous importin a4 is also maternally expressed, but not sufficient to compensate for the lack of importin a7 and its depletion does not cause infertility, suggesting that specific functions of importin a7 are essential for early mouse development. Since importin a5 is a zygotically expressed protein, a whole subfamily of GSK 650394 importins is missing in early importin a7 knockout embryos. This may explain the severity of the phenotype. Recently, a novel member of the a importin family, importin a2, has also been described to be maternally expressed and it was shown that its depletion leads to a comparable phenotype as the importin a7 knockout, a stop in development at the two-cell stage. However, in this case the phenotype is not completely penetrant and half of the embryos reach the blastocyst stage. This maybe due to the fact that importin a2 belongs to the same subfamily of a importins as importin a1, which is also maternally expressed and may therefore partially compensate for the lack of importin a2. Taken together, a importins play important but yet undefined roles in early preimplantation development of mammals. After homologous recombination in embryonic stem cells, exon 2, which bears the translational start site for the importin a7 protein, was deleted. ES cell manipulation was performed as described previously. Briefly, ES cells were electroporated with the linearised construct and after a double selection process with neomycin and gancyclovir, 176 clones were picked. We identified 5 positive clones by PCR of which one was chosen for blastocyst injection. ALS is characterized by progressive paralysis of the muscles of the limbs, speech, swallowing and respiration, due to the progressive degeneration of innervating motor neurons. Certain proteins, mutant and wild-type alike, have been identified to mislocalize or accumulate as microscopically identifiable misfolded aggregates that may Succinylsulfathiazole participate in ALS pathogenesis. Misfolded aggregated proteins and peptides are also thought to participate in prion diseases, such as Creutzfeldt-Jakob, kuru and fatal familial insomnia diseases and other neurodegenerative diseases, including Alzheimer��s disease, Parkinson��s disease, frontotemporal dementia and Huntington��s disease.