HINDLIMB MUSCLE ORGANOGENESIS AND NEURAL INTEGRATION

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Developmentally-caused limb defects constitute a major debilitating disorder. In an attempt to evaluate the extent of variability from the normal pattern of limb development, it is necessary that the various systems contributing to normal limb development be systematically and thoroughly evaluated. It is proposed to study, in depth, the development, maturation and neural integration of hindlimb musculature, with emphasis on the following objectives: 1. Determination of the pattern of organogenesis of the fetal mouse soleus muscle (a predominantly slow twitch muscle). This pattern of development will be compared and contrasted with the pattern of development of the extensor digitorum longus muscle (a fast twitch muscle). 2. Investigation of the complex interrelationship between the developing muscle organ and the nervous system during the fetal and early neonatal stages, including: a. Establishment of the time course and pattern of myoneural integration. b. Investigation of mechanisms which may be involved in the establishment of polyneuronal innervation. c. Correlation of developmental events occurring in fetal muscle with maturational changes in the spinal cord (i.e. programmed motoneuron cell death). 3. Investigation of the time course of myosin transition in developing myofibers of future fast and slow hindlimb muscles, with emphasis of isozyme transitions in single motor units during the period of polyneuronal elimination. In vivo studies of developing muscles of the hindlimb of the 129 ReJ mouse will be carried out using spaced serial, section electron microscopic techniques, computer assisted morphometric analyses, retrograde transport of horseradish peroxidase, physiological and immunocytochemical techniques.