This proposal is an inquiry into the myogenic and neural (efferent and afferent) mechanisms whereby undifferentiated muscle cells are trans- formed into the three types of intrafusal fiber (bag1, bag2, chain) in muscle spindles of the rat. First, the role of myogenic factors in the differentiation of the three types of intrafusal fiber will be examined in medial gastrocnemius muscles reinnervated in the presence of exogenous nerve growth factor following nerve crush at one of three perinatal periods, whereby the types of muscle substrates available for spindle formation at sites of afferent-muscle cell contacts are altered. Second, the role of motor innervation in the assembly of spindles and differenti- ation of intrafusal fibers will be examined in neonatal muscles reinnervated by afferents only following nerve crush and distal spinal cord extirpation at birth. Third, the mechanisms of the morphogenetic effect of afferents will be addressed by surveying sensory nerve terminals in spindles for the expression of neuroactive substances, and by blocking axoplasmic transport in afferents supplying immature spindles in order to determine whether trophic substances emanating from sensory terminals regulate the differentiation of spindles. Light and electron microscopic neuroanatomical and immunochemical techniques are utilized. Particular attention is paid to the effects of experimental manipulations on the expression of myosin heavy chain isoforms which are markers of contractile proteins in intrafusal fibers. The developing spindle is a unique, naturally-occurring model for studying the interactions of three types of cell -- sensory neurons, motor neurons, and muscle cells -- in the course of formation and differentiation of a highly specialized class of muscle fibers. Investigation of afferent-muscle cell interactions addresses a poorly understood area of nerve-muscle interdependence during development. Research into the mechanisms of afferent-muscle interactions may provide evidence in favor of the existence of a sensory neurotrophic factor with a regulatory effect on myosin gene expression in muscle cells.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 2 (NEUB)
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Boston University
Schools of Medicine
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Kucera, J; Fan, G; Walro, J et al. (1998) Neurotrophin-3 and trkC in muscle are non-essential for the development of mouse muscle spindles. Neuroreport 9:905-9
Wright, D E; Zhou, L; Kucera, J et al. (1997) Introduction of a neurotrophin-3 transgene into muscle selectively rescues proprioceptive neurons in mice lacking endogenous neurotrophin-3. Neuron 19:503-17
Kucera, J; Walro, J M (1995) An immunocytochemical marker for early type I muscle fibers in the developing rat hindlimb. Anat Embryol (Berl) 192:137-47
Ernfors, P; Kucera, J; Lee, K F et al. (1995) Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice. Int J Dev Biol 39:799-807
Kucera, J; Fan, G; Jaenisch, R et al. (1995) Dependence of developing group Ia afferents on neurotrophin-3. J Comp Neurol 363:307-20
Kucera, J; Ernfors, P; Walro, J et al. (1995) Reduction in the number of spinal motor neurons in neurotrophin-3-deficient mice. Neuroscience 69:321-30
Ernfors, P; Lee, K F; Kucera, J et al. (1994) Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77:503-12
Kucera, J; Walro, J M (1994) Sequences of intrafusal fiber formation are muscle-dependent in rat hindlimbs. Anat Embryol (Berl) 190:273-86
Kucera, J; Walro, J M; Gao, Y (1993) Fusimotor-free spindles in reinnervated muscles of neonatal rats treated with nerve growth factor. Neuroscience 52:219-28
Kucera, J; Walro, J M (1993) Transient expression of a slow-tonic MHC isoform by extrafusal fibers in the developing rat. Anat Embryol (Berl) 188:409-18

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