Polyuria, Polydipsia, and Poly(A) Tails: Insights into the Adaptive Nature of the Cellular Stress Response Pathways

Abstract

On February 24, 1961, in a private animal house on a remote mountain in Vermont, a Long Evans rat gave birth to 17 young. The animal house assistant noticed that in this one cage the water bottle was nearly always empty; some of the young were drinking excessively, and this could be corrected by giving them the antidiuretic hormone, vasopressin. Four of the young were given to Heinz Valtin and Kurt Benerische at Dartmouth Medical School, who bred from them to generate the line that became famous as the Brattleboro rat. With the help of many collaborators, they soon established that this strain had hereditary hypothalamic diabetes insipidus, resulting from a defect in a single gene (1). In 1984, Schmale and Richter (2) showed exactly what the defect was; there was a single base deletion in the sequence encoding neurophysin, part of the vasopressin precursor protein; this gave rise to an open reading frame and hence a greatly altered precursor protein. It turned out that this aberrant precursor, which contains the normal vasopressin sequence, was not secreted but instead accumulates in the cytoplasm of the magnocellular vasopressin neurons in the supraoptic and paraventricular nuclei of the hypothalamus. Despite this, the vasopressin neurons of the Brattleboro rat are in many ways normal. Electrophysiologically, they look very much like normal vasopressin cells, they respond normally to osmotic challenge (3), and indeed the phenotype of the Brattleboro rat can be rescued by adeno-associated viral-mediated gene transfer to restore normal vasopressin expression in the defective vasopressin neurons (4). The Brattleboro rat provided opportunities for fundamental research that were unparalleled in the era before transgenic knockout animals, and these were avidly taken. But as a model for human disease, the Brattleboro rat seemed to be less useful. Diabetes insipidus is a rare disease in humans and can reflect either the absence of vasopressin secretion (central diabetes insipidus) or insensitivity to vasopressin at the level of the kidney (nephrogenic diabetes insipidus). Inpatientswithfamilialdiabetes insipidus(FNDI) of central origin, the genetic defect is usually in the neurophysin-coding region of the vasopressin gene as is the case in the Brattleboro rat (5). However, in affected individuals, severe disease symptoms usually appear only months or years after birth, despite the presence of one normal allele; by contrast, the heterozygous Brattleboro rat never develops symptoms of diabetes insipidus, whereas in the homozygous Brattleboro rat, the defects are present at birth. Many of these mutations that cause FNDI interfere with neurophysin folding and/or dimerization; the mutated precursor cannot be targeting to the regulated neurosecretory granules and is retained in the lumen of the endoplasmic reticulum (ER) (6, 7). In the relatively few cases of human FNDI where autopsy reports are available, neuronal loss is apparent in the magnocellular cells of the hypothalamus; the vasopressin neurons appear to have died, and hence, it has been assumed that the abnormal protein product of the defective allele is toxic to the neurons. As neurons begin to die off, a deficiency in vasopressin secretion is exacerbated, leading to exacerbated osmotic imbalance and increased stimulation of hormone synthesis and hence an increased rate of production of the toxic precursor in the surviving cells, speeding their demise. Thus, at a critical point, this vicious cycle leads to relatively sudden collapse of vasopressin production re-