Expression of insulin-like growth factor-I in transgenic mice.

The studies reviewed above provide strong evidence for the concept that IGF-I plays an essential role in mediating the growth-promoting actions of GH, and thus, they support the central elements of the "somatomedin hypothesis." The data, however, also point to actions of each GH and IGF-I that are not linked. Many hormones and factors, other than GH, are known to regulate the expression of IGF-I, as well as its binding proteins (modulators of its actions), in a tissue-specific fashion. Some of these influences, e.g., estrogens, thyroid hormone, and nutritional factors, also effect GH synthesis and/or secretion. This complex and precise regulation undoubtedly plays a key role in coordinating the somatic and visceral growth stimulated by GH and IGF-I. The evidence that GH and IGF-I actions are not always coupled, therefore, is not surprising. The challenge is to dissect the precise role(s) of GH and IGF-I, as well as other hormones and growth factors, in the control of growth. Study of transgenic animals provides a powerful way to approach these issues in vivo. These studies demonstrate that IGF-I is capable of stimulating in vivo brain growth. The transgene IGF-I-stimulated increase in brain size appears to result both from an increase in cell number and, as demonstrated by Carson et al., from an increase in myelin content, which in turn may result from proliferation of oligodendrocytes. Other roles for IGF-I in brain growth and development, however, are possible and amply supported by numerous studies of brain-derived cultured cells (see other papers herein). Because IGF-I is normally expressed in brain, it seems reasonable to assume that the IGF-I-stimulated brain growth observed in these transgenic mice represents a response to IGF-I overexpression rather than a pharmacologic response that is not indicative of a normal IGF-I function. Study of this IGF-I transgenic line cannot address the developmental period(s) when IGF-I normally stimulates brain growth, but this transgenic line provides a model to investigate IGF-I's specific role and its mechanisms of action.