Background - Mutations Affecting Motor Function
Motor control pathways - Locomotion requires a coordinated function of several cortical and subcortical brain structures that range from the basal ganglia and cortical motoneurons to spinal interneurons and motoneurons [77-79]. We describe screens for mutants with defects in any critical point in this pathway, including: cortical and brainstem motor initiation, cerebellar-controlled coordination of motor behavior, signal transduction within the spinal cord and peripheral nervous system, and translation of that signal to controlled muscle contraction.
Genetics of cerebellar anomalies - The cerebellum helps to maintain posture, regulate muscle tone and coordinate movement. Ataxia, (incoordination of gait or limb movements), is the most characteristic sign of disrupted cerebellar function. Other signs include axial and limb tremors, limb hypotonia, dysarthria and ocular motor abnormalities. These symptoms develop in both degenerative and congenital syndromes, many of which have a heterogeneous but genetic basis (e.g. OPCA [80]), but few of the causative molecular defects have been identified. Cerebellar defects also underlie congenital ataxias [81, 82]. These predominantly non-progressive syndromes are often accompanied by developmental delay of speech and motor skills. Such syndromes include posterior fossa developmental problems that include the cerebellum (e.g. Dandy-Walker syndrome), neuronal migration defects (e.g. Zellweger's Syndrome and Fukuyama type congenital muscular dystrophy) and other ataxic syndromes without brain malformation (e.g. Angelman syndrome). A variety of cerebellar disorders are readily identifiable in the mouse, making the isolation of respective genes ideal for studies on brain development and degeneration, as well as on structure/function relationships. Most of the spontaneous mutants with motor dysfunction arose and were initially characterized at JAX. Overall, analysis of several spontaneous and induced mutations that perturb cerebellar development has given great insight into the genes controlling the formation of the cerebellum and its boundaries, (e.g. swaying/Wnt1, En1-2, Pax2, rcm), neuron differentiation (e.g. Math1), and migration of cerebellar neurons (e.g. reeler, scrambler/disabled). Analysis of mouse mutants has also lead to the identification of molecules necessary for survival of cerebellar cells (e.g., weaver, staggerer, lurcher) or other cerebellar neurons (e.g. swe) [83, 84]. While these models have provided important information, many molecular mechanisms underlying cerebellar development are still not well understood. Although there are some transgenics and knockouts for late-onset ataxia (e.g. SCA1, Prp, cystB), there are few when compared to humans [85-87].
Genetics of neuromuscular diseases - Defective motor-system components lead to a number of diseases in humans including motor neuron (e.g. ALS, SMA), hereditary peripheral neuropathies, autoimmune neuropathies (e.g. myasthenia gravis and MS), ion-channel disorders and myopathies such as Duchenne and Becker muscular dystrophy (DMD, BMD) [88]. While positional cloning is identifying some common forms of these diseases, rare autosomal recessive and sporadic cases remain largely inaccessible to geneticists. Also, genetic heterogeneity observed in familial cases of diseases such as ALS and in sporadic cases suggest that several different genes are necessary for the normal function and survival of motor neurons [89]. Approximately 40 neuromuscular diseases are targeted for research by the Muscular Dystrophy Association [90], and well over 200 independent genetic disorders are cross-referenced in the OMIM database - a likely underestimate of the true figure since only those with sufficient data for clear inheritance are included. Mouse neuromuscular mutations have been identified at JAX over the years, including dystrophia muscularis (Lama2dy), myodystrophy (myd), muscular dystrophy with myositis (mdm), generalized neuroaxonal dystrophy (gnd), and neuromuscular degeneration (nmd) [91-96], comprising many clinically relevant disease categories including progressive muscular dystrophies, peripheral neuropathies, axonal dystrophies and motor neuron diseases. However, few have a disease onset later than 6 months. The few exceptions include motor neuron degeneration (mnd) [97, 98], and the mdx mouse model of DMD, which is fertile and has no visible symptoms for its 2-yr lifespan [99]. We have used mdx to understand the molecular mechanisms of muscle degeneration and as a model for potential gene or drug therapies [100-103].
