Development of oligodendrocytes and the generation of myelin internodes within the spinal cord depends on regional signals derived from the notochord and axonally derived signals. Neuregulin 1 (NRG)-1, localized in the floor plate as well as in motor and sensory neurons, is necessary for normal oligodendrocyte development. Oligodendrocytes respond to NRGs by activating members of the erbB receptor tyrosine kinase family. Here, we show that erbB2 is not necessary for the early stages of oligodendrocyte precursor development, but is essential for proligodendroblasts to differentiate into galactosylcerebroside-positive (GalC+) oligodendrocytes. In the presence of erbB2, oligodendrocyte development is normal. In the absence of erbB2 (erbB2−/−), however, oligodendrocyte development is halted at the proligodendroblast stage with a >10-fold reduction in the number of GalC+ oligodendrocytes. ErbB2 appears to function in the transition of proligodendroblast to oligodendrocyte by transducing a terminal differentiation signal, since there is no evidence of increased oligodendrocyte death in the absence of erbB2. Furthermore, known survival signals for oligodendrocytes increase oligodendrocyte numbers in the presence of erbB2, but fail to do so in the absence of erbB2. Of the erbB2−/− oligodendrocytes that do differentiate, all fail to ensheath neurites. These data suggest that erbB2 is required for the terminal differentiation of oligodendrocytes and for development of myelin.

Patients with Paget's disease of bone were found to have elevated serum levels of type I procollagen carboxyterminal peptide (pColl-I-C) which correlated with other measurements of disease activity. The elevated levels of pColl-I-C decreased within hours after the injection of salmon calcitonin and within weeks after oral dichloromethylene diphosphonate treatment. The decrease in serum pColl-I-C after a single injection of salmon calcitonin was associated with a decrease in urinary hydroxyproline excretion, both of which rose toward pretreatment values within 7 h. The pColl-I-C levels remained normal for months after dichloromethylene diphosphonate therapy was discontinued. Using a RIA for the type III procollagen amino-terminal peptide (pColl-III-N), it was found that serum levels were also elevated in patients with Paget's disease. The levels of pColl-III-N also decreased after the injection of salmon calcitonin, but not to the same extent as those of pColl-I-C. After chronic therapy with dichloromethylene diphosphonate, serum levels of pColl-III-N decreased, but not into the normal range. We postulate that whereas pColl-I-C is derived from synthesis of mineralized bone collagen, pColl-III-N is derived from the loose fibrous stroma replacing marrow in areas closely associated with active Pagetic bone disease.

Thyroid hormone (T3 and T4) down-regulation of TSH subunit steady state mRNA levels and subunit gene transcription in vitro and in vivo has been well studied. We present evidence here that T3 can also regulate the turnover of TSH subunit mRNA. The apparent half-life of the TSH beta-subunit mRNA was determined by adding actinomycin-D (2 microM) to dispersed rat pituitary cultures in hypothyroid medium or medium containing 10(-7) M T3 and analyzing the decline in subunit mRNA levels with time. The half-life of the TSH beta mRNA from those cultures treated with T3 was shorter than that of the control cultures (9 vs. greater than 24 h, respectively). A possible mechanism by which TSH beta-subunit mRNA stability is altered is through a change in the size of each mRNA's poly(A) tail. Northern blot analysis of total RNA from the above cultures revealed that T3 treatment reduces the size of the TSH beta-subunit mRNA. To determine if this alteration of mRNA size was due to a loss of a portion of the poly(A) tract and not to alternative splicing of the transcript or use of a secondary transcriptional start site, pooled RNAs were hybridized with oligo(dT) and subsequently digested with RNAse-H to remove the poly(A) tract. RNA blot analysis of these RNAs showed that T3 treatment results in the loss of most of the TSH beta poly(A) tail.(ABSTRACT TRUNCATED AT 250 WORDS)

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Neu differentiation factor (NDF, also called neuregulin) is a potent inducer of epithelial cell proliferation and has been shown to induce mammary carcinomas in transgenic mice. Notwithstanding this proliferative effect, we have shown that a novel isoform of NDF can induce apoptosis when overexpressed. Here we report that this property also extends to other NDF isoforms and that the cytoplasmic portion of NDF is largely responsible for the apoptotic effect, whereas the proliferative activity is likely to depend upon the secreted version of NDF. In accordance with these contradictory properties, we find that tumors induced by NDF display extensive apoptosis in vivo. NDF is therefore an oncogene whose deregulation can induce transformation as well as apoptosis.

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