Roles of ETS Genes ER81 and PEA3 in the Development of the Monosynaptic Stretch Reflex Circuit

Ladle, David R (2002) Roles of ETS Genes ER81 and PEA3 in the Development of the Monosynaptic Stretch Reflex Circuit. Doctoral Dissertation, University of Pittsburgh.

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Abstract

The monosynaptic stretch reflex circuit consists of two neural cell types, sensory neurons and alpha-motoneurons. Ia afferents form synaptic connections with motoneurons projecting to the same or synergistic muscles, but not with motoneurons projecting to unrelated muscles. These synaptic connections form appropriately from the outset suggesting that they may be controlled by expression of specific adhesion molecules in matching sensory and motor neurons. Recently, two ETS-family transcription factors (Er81 and PEA3) were shown to be expressed in subsets of motoneurons and muscle sensory neurons. The expression patterns of these factors suggested that ETS genes might regulate the formation of synaptic connections between Ia afferents and motoneurons. This thesis explores the roles of Er81 and PEA3 in the formation of the stretch reflex circuit inferred from a study of Er81 and PEA3 null-mutant mice.Analysis of Er81 null-mutant mice revealed that Er81 controls a late step in Ia afferent axon guidance. Ia afferents induce the development of muscle spindles in the periphery and project axons into the spinal cord, but fail to grow axon collaterals into the ventral spinal cord where normally strong monosynaptic connections are formed with motoneurons. Consequently, monosynaptic Ia afferent inputs to motoneurons are greatly reduced in these mice. This severe phenotype precluded determination of whether or not the pattern of remaining Ia afferent inputs was normal.Intracellular recordings from quadriceps and obturator motoneurons in PEA3 null-mutants, however, revealed that functionally appropriate patterns of Ia afferent input to motoneurons develop normally in the absence of PEA3. PEA3 mutant mice demonstrated a role for PEA3 in the formation of a specific motor pool. Cutaneous maximus muscle motoneurons normally express PEA3. In PEA3 mutants, the majority of these motoneurons fail to migrate and coalesce appropriately into a discrete motor pool. These motoneurons also fail to project axons into the c. maximus muscle. Consequently, the muscle is atrophic.Thus, Er81 and PEA3 contribute to key developmental stages in the formation of the stretch reflex circuit: the growth of Ia afferents axons toward motoneurons and the formation of appropriate motor pool targets.

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