The author has declared that no competing interests exist.
The external features of our bodies are specified in the embryo and then grow for some 16 years, yet many are remarkably symmetrical. Just consider how similar in size and shape your two ears are. And if you extend your arms, you will likely find that they, too, are similar in length, even though they grew independently from tiny buds in the embryo. Their length matches with an accuracy of about 0.2% yet there is no known communication between the limbs during growth. You'll find the same holds for your two forefingers as it does for the size of internal body organs such as the kidneys and lungs. How is such coordination achieved? While we have a reasonably good understanding of how our limbs grow, we know relatively little about how their growth is so reliably controlled.
Organ size in animals is determined by both intrinsic developmental programs and by extracellular factors that stimulate or inhibit growth, but the relative importance of these two mechanisms in different organs varies a good deal
By contrast, the thymus is controlled by intrinsic growth control mechanisms. We know this because when multiple fetal thymus glands are transplanted into a developing mouse embryo, each one grows to full size, indicating a primarily intrinsic control. Another illustration of an intrinsic growth program comes from grafting limb buds between large and small species of salamanders of the genus
The development of symmetry in limb buds in the embryo appears to depend on the presence of positive signalling feedback loops during limb bud growth
Only an intrinsic growth programme can explain the control of limb growth as the growing region in the bones because there is no evidence that the growth plates have a means of sensing how much the bone has grown. While, in principle, bones could secrete circulating factors affecting growth in the plates, there is no evidence for this. Moreover, in growth plate–transplantation experiments, the growth rate of the transplanted growth plate depends on the age and hence the size of the donor animal, not on that of the recipient.
The growth plates extend the bone but they remain about the same size for many years, as the cartilage cells they produce are replaced by bone (
The growth plates are cartilaginous regions that lie between the epiphysis of the future joint and the central region of the bone, the diaphysis. In the figure, bone has already replaced cartilage in the diaphysis, and more bone is being added at the growth plates. Within the growth plates, cartilage cells multiply in the proliferative zone, then mature and undergo cell enlargement and extend the bone. They are then replaced by bone
A high growth rate in limbs is observed from fetal life, with a rapid deceleration up to about three years of age. The second phase is characterized by a period of lower, slowly decelerating growth velocity up to puberty. The last phase, puberty, is characterized by an increased rate of longitudinal growth until the age of peak height velocity has been reached. Then, growth velocity rapidly decreases due to growth plate maturation in long bones and spine, leading to growth plate fusion and cessation of longitudinal growth. Growth continues through childhood but gets slower until there is a spurt at adolescence, mainly due to an increase in the size of the hypertrophied cells, after which growth ceases and the growth plate fuses and disappears. At a single stage during growth, plates in different bones can elongate at rates that differ by a factor of seven or even more. Even the growth plates at the ends of the same bone can elongate at significantly different rates, again consistent with an intrinsic programme. Fusion of the growth plate is a result, and not the cause of ceased growth. When growth stops, the plate disappears. Epiphyseal fusion is triggered when the proliferative potential of growth plate chondrocytes is exhausted; and estrogen does not induce growth plate ossification directly, but accelerates the programmed senescence of the growth plate, thus causing earlier proliferative exhaustion and consequently earlier fusion.
The number of cells in a column is of the order of 40. Cells can be produced at rates of over 10,000 a day, yet the number of cells needs to be identical (or very nearly so) on both limbs for years. In a typical rat growth plate eight chondrocytes leave each growth plate column each day and are replaced by cells at the top of the column. Thus, increase in length of the bone, which can occur with columns keeping the same length, is due mainly to hypertrophy and cell proliferation. The rate of increase in length due to a growth plate is equal to the rate of new cell production for each column in the proliferative zone multiplied by the mean height of the hypertrophied cells. Different growth plates in the limb provide growth at different rates, and this can be due to differences in the size of the proliferative zone and the rate of cell proliferation, as well as the degree of cell enlargement when the cells hypertrophy. In the rat proximal tibia plate, the number of new cells per day is 16,400 with a standard deviation of 5,850, the cell cycle time is roughly 30 hours, and height of the columns is about 620 microns
The lengths of proliferative columns in individual bones are controlled by the growth factors PTHrP and Indian hedgehog (Ihh)
The major systemic hormones that regulate longitudinal bone growth during childhood are GH and IGF-1, thyroid hormone (T3 and T4), and glucocorticoids (GC), whereas during puberty the sex steroids (androgens and estrogens) contribute a great deal to this process
According to the current view, growth ceases because the cartilage cells have a finite growth potential
Given the complex interactions and signals in the growth plate, it is all the more remarkable that the intrinsic growth programmes of the different growth plates on the two sides of the body manage to produce arms of the same length with such precision and reliability. It's possible that the large number of cells in a growth plate favour reliable growth by reducing any effect of small differences in cell behaviour. One might test this possibility by running computer simulations of the growth plate to see whether the large number of cells in a growth plate would yield a reliable and consistent growth, in spite of any small variations in cell behaviour.
It would also be helpful to compare the cell dynamics in growth plates on left and right limbs to determine just how similar they are. Are the cell cycle times and number of dividing cells the same? Are the column lengths identical? Are the sizes of the three main regions along the columns the same? If cell proliferation in a growth plate is blocked for any period of time, do the bones reach the same final length on both sides? If some of the cells are killed does the bone grow shorter? And if a growth plate is replaced by a younger plate, does the length of the bone end up longer than that on the other side? As we investigate these questions and gain a better understanding of the signals controlling limb growth and size, we will, in turn, elucidate the intrinsic growth programme that endows us with remarkably symmetrical limbs. Solving this problem would provide major insights into growth control and will no doubt keep us busy seeking its solution for a good long while.