Transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumour masses

The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.

Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity

Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1–binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation–induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.

The tissue-specific regulation of the carboxyl ester lipase gene in exocrine pancreas differs significantly between mouse and human

The carboxyl ester lipase (CEL) gene is highly expressed in exocrine pancreas and expression of the human CEL gene is mediated by a strong tissue-specific enhancer, which is absolutely necessary for high-level expression. The mouse promoter, on the other hand, does not contain a corresponding enhancer element, but instead is totally dependent on another pancreas-specific element. This element is identified as a pancreatic transcription factor 1 (PTF 1)-binding site. The human CEL promoter also contains a putative PTF 1 element located at a position corresponding to the essential PTF 1 site in the mouse promoter. However, nucleotide changes in the human promoter 5´ flanking this PTF 1 site have created an overlapping CCAAT/enhancer-binding protein (C/EBP)-like binding motif, interfering with the binding of PTF 1. Hence, our findings provide an example of genetic divergence between species not accompanied by difference in function.

Structural determinant of the species-specific transcription of the mouse rRNA gene promoter.

Mammalian ribosomal DNA (rDNA) transcription has a certain species specificity such that, both in vivo and in vitro, human rDNA cannot be transcribed by mouse machinery and vice versa. This is due to a species-dependent transcription factor, TFID (Y. Mishima, I. Financsek, R. Kominami, and M. Muramatsu, Nucleic Acids Res. 10:6659-6670, 1982). On the basis of the information obtained from 5' and 3' substitution mutants, we prepared a chimeric gene in which the mouse sequence from positions -32 to -14 was inserted into the corresponding location of the human rDNA promoter. The chimeric gene could be transcribed by mouse extracts nearly as efficiently as the wild-type mouse promoter. The chimeric gene could also sequester transcription factor TFID at an efficiency similar to that for the mouse promoter. Partially purified mouse TFID that could not protect the human rDNA promoter against DNase I produced a clear footprint on this chimeric gene that was similar to that on mouse rDNA promoter. The basic structure of the mouse rDNA core promoter is discussed in relation to the interaction with TFID.

Structural determinant of the species-specific transcription of the mouse rRNA gene promoter

Mammalian ribosomal DNA (rDNA) transcription has a certain species specificity such that, both in vivo and in vitro, human rDNA cannot be transcribed by mouse machinery and vice versa. This is due to a species-dependent transcription factor, TFID (Y. Mishima, I. Financsek, R. Kominami, and M. Muramatsu, Nucleic Acids Res. 10:6659-6670, 1982). On the basis of the information obtained from 5' and 3' substitution mutants, we prepared a chimeric gene in which the mouse sequence from positions -32 to -14 was inserted into the corresponding location of the human rDNA promoter. The chimeric gene could be transcribed by mouse extracts nearly as efficiently as the wild-type mouse promoter. The chimeric gene could also sequester transcription factor TFID at an efficiency similar to that for the mouse promoter. Partially purified mouse TFID that could not protect the human rDNA promoter against DNase I produced a clear footprint on this chimeric gene that was similar to that on mouse rDNA promoter. The basic structure of the mouse rDNA core promoter is discussed in relation to the interaction with TFID.