Differential inhibition of postnatal brain, spinal cord and body growth by a growth hormone antagonist

Abstract

Background: Growth hormone (GH) plays an incompletely understood role in the development of the central nervous system (CNS). In this study, we use transgenic mice expressing a growth hormone antagonist (GHA) to explore the role of GH in regulating postnatal brain, spinal cord and body growth into adulthood. The GHA transgene encodes a protein that inhibits the binding of GH to its receptor, specifically antagonizing the trophic effects of endogenous GH.

Results: Before 50 days of postnatal age, GHA reduces spinal cord weight more than brain weight, but less than body weight. Thereafter, GHA ceases to inhibit the increase in body weight, which approaches control levels by day 150. In contrast, GHA continues to act on the CNS after day 50, reducing spinal cord growth to a greater extent and for a longer duration than brain growth.

Conclusions: Judging from its inhibition by GHA, GH differentially affects the magnitude, velocity and duration of postnatal growth of the brain, spinal cord and body. GH promotes body enlargement more than CNS growth early in postnatal life. Later, its CNS effects are most obvious in the spinal cord, which continues to exhibit GH dependence well into adulthood. As normal CNS growth slows, so does its inhibition by GHA, suggesting that reduced trophic effects of GH contribute to the postnatal slowing of CNS growth. GHA is a highly useful tool for studying the role of endogenous GH on organ-specific growth during aging.

Figure 1

Body weights of male and female GHA and WT mice between 21 and 150 days of age Mean body weight (± SD) are shown for an average of 12 animals from different litters at each time point. Differences between GHA and WT mice of each gender were significant to at least p < 0.05 at each age analyzed.

Figure 2

Age-dependent changes in body weight of GHA mice relative to WT littermate controls Data are expressed as a mean percent of WT values ± SEM. Note the loss of effective inhibition of body growth by GHA after 50 days of age in both male and female mice.

Figure 3

Brain weights in GHA and WT mice between 21 and 150 days of age. Mean brain weights (± SD) are shown for an average of 7 animals (sexes combined) from different litters at each time point. *p < 0.05; **p < 0.01

Figure 4

Spinal cord weights in GHA and WT mice between 21 and 150 days of age. Mean spinal cord weights (± SD) are shown for an average of 7 animals (sexes combined) from different litters at each time point. *p < 0.05; **p < 0.01

Figure 5

Age-dependent change in brain and spinal cord weight of GHA mice relative to WT littermate controls Data are expressed as a mean percent of WT values ± SEM. Note that GHA continues to reduce spinal cord after postnatal day 50, but has little, if any, further effect on brain size. First-order regression analyses showed a significant (p < 0.01) correlation between age and the y-axis values for the spinal cord (R = 0.97), but no significant correlation for the brain (R = 0.26).

Figure 6

Comparison of body and CNS growth in transgenic mice with increased and decreased GH action Mean percent changes (± SD) reported for GH+ [7] and GH null mice [6,11] are compared with data from the present study. The average age of the mice was 65 ± 9 days. Note that the rank order of GH and GHA effects on growth is the same in all three experimental situations.

Figure 7

Body weight as a phenotypic marker for pooled litters of GHA and WT mice No overlap between the lower body weights of GHA (left) and heavier WT (right) mice was observed for either 50 day-old male (shown here) or female mice. The mean body weight (± SD) for GHA males at 50 days was 13.4 ± 1.2 g versus 24.2 ± 1.4 g for WT males.