Spicer, Andrew Paul; (1993) Functional and evolutionary analysis of the mouse Muc-1 gene. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mouse homologue of the human tumour-associated mucin, MUC1, was cloned and full-length sequence was determined. This mucin (previously called polymorphic epithelial mucin) is expressed by the majority of simple secretory epithelial cells in both the mouse and human and is also overexpressed in a large percentage of carcinomas. The mouse gene, Muc-1, encodes an integral membrane protein with 44% of its coding capacity made up of serine, threonine and proline, a composition typical of a highly O-glycosylated protein. The Muc-1 core protein consists of an amino-terminal signal sequence, a repetitive domain encoding 16 repeats of 20-21 amino acids, and unique sequence containing membrane-spanning and cytoplasmic domains. Although overall homology with the human MUC1 protein is only 53%, the transmembrane and cytoplasmic domains exhibit homologies of 90% and 87%, respectively. This level of sequence conservation would suggest that these regions may be functionally important. Interestingly, the mouse homologue, unlike its human counterpart does not exhibit a variable number tandem repeat (VNTR) polymorphism. However, this type of polymorphism was found to be present in all other mammalian groups analysed. Data is presented, including sequence obtained for the Muc-1 gene from a large number of species, to suggest how this gene has evolved and to explain possible reasons why the mouse Muc-1 gene does not exhibit minisatellite characteristics. Numerous functions have been suggested for this molecule, yet it still remains unclear what role this protein plays in the tissues and tumours in which it is expressed. In an effort to learn more of the function of the mouse Muc-1 gene, the gene was specifically mutated in embryonic stem (ES) cells. Targeting vectors derived through genomic clones from two strains of mice were utilised and their relative targeting efficiencies are discussed. Several mouse cell lines were created carrying a disruption in the Muc-1 gene. These cell lines were injected into nude mice to create tumours and also injected into blastocysts, in order to generate mice carrying the Muc-1 mutation. These mouse lines will provide a crucial tool in the analysis of the function of this molecule in vivo.

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