Human familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant endocrine disorder that presents in early childhood as excessive drinking and urination as a consequence of a progressive loss of secretion of vasopressin (VP) from posterior pituitary nerve terminals. Mutations in the VP gene have been implicated as the cause of FNDI, but the mechanisms by which these mutants manifest their pathology, and prevent the secretion of the co‐expressed wild‐type protein, are unknown. One hypothesis suggests that mutant precursors are toxic, and stop the synthesis of wild‐type VP by killing expressing cells. Another hypothesis suggests that aberrant interactions between mutant and wild‐type precursors might directly inhibit the elaboration or secretion of the products of the normal allele. We have tested these hypotheses using new animal models‐‐transgenic rats that express an FNDI mutant VP gene that encodes a truncated precursor (Cys67stop). Cell‐specific and inducible expression of the Cys67stop mutation in rat VP hypothalamic neurons does not result in cell death or atrophy. Rather, expression of the FNDI mutant causes a neuronal pathology characterized by distorted structures in the cell body that are labeled by antisera that recognize endoplasmic reticulum (ER) markers, and that accumulate both mutant and wild‐type VP gene products. This is accompanied by an increase in the abundance of the mannose‐6‐phosphate receptor (MPR), a marker of endosome‐lysosome activity. We suggest that FNDI in humans may be initiated, as in our transgenic rat model, by the trapping of wild‐type VP gene products within an ER, which is targeted for lysosomal degradation by autophagy.

Transgenic experiments can be used to test the extent to which genes from different species can be swapped around, but still retain function, and be appropriately regulated. A vector has been developed that directs the expression of foreign genes to specific groups of vasopressin (VP) hypothalamic neurons in transgenic rats. Using this vector, we have expressed the bovine VP (bVP) RNA in the rat brain. In contrast to the situation in a mouse host, but like its endogenous rat counterpart, the mRNA encoded by the bVP transgene is subject to posttranscriptional physiological regulation in the hypothalamus; its poly(A) tail dramatically lengthens as a consequence of 3 days of dehydration. Transgene expression is also seen in the adrenal cortex, but here, despite a marked increase in transgene RNA levels with dehydration, there is no change in poly(A) tail length. These data suggest that the mouse hypothalamus and the rat adrenal gland do not have the transcript recognition or enzymatic machinery required for the physiologically responsive poly(A) tail length modulation seen in the rat brain.