Mice Lacking The Pax8 Gene Suffer From Hypothyroidism And Fail To FormThyroxin-Producing Cells Of The Thyroid Gland

May 14, 1998

In the May issue of Nature Genetics, Scientists at the Max Planck Institute for Biophysical Chemistry, Goettingen, Germany report on the generation of a mouse mutant lacking the Pax8 gene. These mice suffer from hypothyroidism, implicating Pax8 as the major player in the formation of the thyroxin producing cells of the thyroid gland.

1:5000 to 1:3000 individuals suffer from hypothyroidism due to malformations of the thyroid gland. Little is known about the molecules involved in the formation of the thyroid. Among a few others, the Pax8 gene is active throughout the development of this organ. The finding that mice lacking the functional Pax8 protein develop hypothyroidism may indicate similar defects in human patients. Researchers at the Department of Molecular Cell Biology, MPI for Biophysical Chemistry, Goettingen, Germany, report their findings in the May issue of Nature Genetics (vol. 19 (1) May 1998).

The Pax8 gene (Paired box-containing) encodes a protein which can bind to DNA and activate transcription. It belongs to a family of proteins (nine members in mice and man) which have been shown to participate in the formation of different organs including the eyes, kidneys and the pancreas.

A year ago, the same department led by Prof. Peter Gruss published two reports in Nature indicating the role of members of the same family of genes, Pax4 and Pax6, in the generation of specific cells in the pancreas (Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G. and Gruss, P., Nature, vol. 386, 27 March 1997; St-Onge,L., Sosa-pineda,B., Chowdhury,K., Mansouri,A. and Gruss,P., Nature, vol. 387, 22 May 1997). The pancreas is composed of two major cell types: the exocrine cells or acini, produce digestive enzymes like amylase, trypsin, nucleases, etc., while the endocrine cells produce insulin, glucagon, somatostatin and other hormones. The generation of mice lacking Pax4 and Pax6, demonstrated that these genes are needed to make insulin- or glucagon-producing cells respectively. Mice without Pax4 and Pax6 have no endocrine cells in the pancreas. In the report in the May issue of Nature Genetics (Mansouri, Chowdhury and Gruss), the authors went on to generate mice with no functional Pax8 protein. The mutant mice develop to term and die within the first three weeks after birth. The thyroid gland does not develop normally and serum concentration of the T4 hormone is very reduced as compared to wild-type mice. Treatment of the mutant mice with thyroxin prolong their survival up to six months, indicating that lethality is due to a defect in the thyroid. Analysis of the thyroid gland indicated that the organ is severely affected.

The thyroid gland is normally composed of two cell types. The first cell type constitutes the major part of the gland and are known as follicular cells which produce the thyroid hormones. The second cell type consists of the parafollicular calcitonin-producing C-cells which constitute a minor component of the normal thyroid. The greater part of the thyroid gland of the mutant embryo is composed of C-cells, and no T4-producing cells are present. The mutation of the Pax8 gene thus affects the major part of the organ, which produces the thyroid hormones.

Early diagnosis and therapy of hypothyroidism is critical because, if untreated, affected children develop irreversible debility and cretinism. The finding that Pax8 is necessary for the formation of thyroxin producing cells in the thyroid gland provides one marker to screen patients with hypothyroidism. The role of Pax8 in the determination of a specific cell type of the thyroid gland may indicate that this gene is, perhaps, also involved in thyroid cancer. Further studies are necessary to investigate this question.


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