The response of motoneurons to neurotrophins

The ongoing search for neurotrophic factors for motoneurons has led to the identification of a number of molecules which regulate motoneuron survival and function. Among these factors, the neurotrophins brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4/5 but not nerve growth factor (NGF), can prevent embryonic and postnatal motoneuron cell death in a variety of experimental paradigms. Analysis of expression of p75, trkB and trkC—components of the neurotrophin receptors—supports a potential physiological role for these factors as muscle- and glial-derived trophic factors for motoneurons. However, the survival of motoneurons during embryonic development is not reduced in the absence of BDNF, NT-3 or NT-4, as revealed by gene knockout experiments. This points to the involvement of additional trophic factors in the regulation of embryonic and postnatal motoneuron survival. The purpose of this review is to bring together the often prophetic observations from earlier studies—prior to the identification and characterization of these neurotrophins—with more recent results. Special issue dedicated to Dr. Hans Thoenen.     

Nebulin isoforms of extraocular muscle

The extraocular muscles (EOMs), which are responsible for reflexive and voluntary eye movements, have many unique biochemical, physiological, and ultrastructural features that set them apart from other skeletal muscles. For example, rodent EOMs lack M-lines and express EOM-specific myosin heavy chain (MYH13) and α-cardiac myosin heavy chain. Recent gene-expression profiling studies indicate the presence of other cardiac-specific proteins in adult EOMs. This interesting mixture of myofibrillar and cytoskeletal proteins poses the questions as to whether nebulette, as opposed to nebulin, might be expressed in EOM, and what isoforms of titin are expressed in the EOM. We have performed gel electrophoresis and immunological analyses to determine the titin and nebulin isoforms expressed in the EOM. We have found that the mass of the titin isoforms expressed in the EOM most closely resemble those found in the skeletal muscles tested, viz., the soleus and extensor digitorum longus (EDL). We also demonstrate that, although the EOM expresses cardiac isoforms of myosin, it does not express nebulette and contains a nebulin isoform with a mass consistent with that found in the prototypical fast hindlimb muscle EDL. This work was supported by grants from NIH-NHLB HL073089 to C.L.M. and NEI/NIH EY12998 to F.H.A.     

The occurrence of muscle spindles in extraocular muscles of various vertebrates

Extraocular muscles from representative species of vertebrate groups ranging from amphibians to the higher mammals were examined in serial histological sections for the presence of muscle spindles. These observations and data from the literature indicate that extraocular muscles of the pig, calf, sheep and other even-toed ungulates are richly supplied with well-defined spindles having a generous complement of intrafusal fibers distinguishable as nuclear bag and chain fibers. Spindles in human eye muscles are also numerous. In macaque and chimpanzee muscles a few poorly developed spindles were present in some, but not all, muscles. No encapsulated receptors were found in 20 other mammalian and submammalian species examined in this study. When present, spindles tended to be located in the zone of small muscle fibers found along the orbital surface of the muscle. Rectus and oblique muscles in all species had such a zone, so that its existence did not determine whether spindles would occur.     

The dendritic architecture of motoneurons: A case study

Within a historical perspective, different experimental approaches are reviewed that have used new tools and new concepts to gain an insight into the functional significance of the architecture of dendritic arborizations of nerve cells. A single type of neurons, the motoneurons, were taken as a case study to show how different fields, such as histology, morphology, electrophysiology, and neuronal modeling, have developed in parallel and accumulated a wealth of new data, and how consideration of these new informations led to new working hypotheses. Matching geometrical and electrical parameters of dendrites is critically analyzed as a basis for understanding of the dendritic functions.     

Microanatomy of adult zebrafish extraocular muscles

Binocular vision requires intricate control of eye movement to align overlapping visual fields for fusion in the visual cortex, and each eye is controlled by 6 extraocular muscles (EOMs). Disorders of EOMs are an important cause of symptomatic vision loss. Importantly, EOMs represent specialized skeletal muscles with distinct gene expression profile and susceptibility to neuromuscular disorders. We aim to investigate and describe the anatomy of adult zebrafish extraocular muscles (EOMs) to enable comparison with human EOM anatomy and facilitate the use of zebrafish as a model for EOM research. Using differential interference contrast (DIC), epifluorescence microscopy, and precise sectioning techniques, we evaluate the anatomy of zebrafish EOM origin, muscle course, and insertion on the eye. Immunofluorescence is used to identify components of tendons, basement membrane and neuromuscular junctions (NMJs), and to analyze myofiber characteristics. We find that adult zebrafish EOM insertions on the globe parallel the organization of human EOMs, including the close proximity of specific EOM insertions to one another. However, analysis of EOM origins reveals important differences between human and zebrafish, such as the common rostral origin of both oblique muscles and the caudal origin of the lateral rectus muscles. Thrombospondin 4 marks the EOM tendons in regions that are highly innervated, and laminin marks the basement membrane, enabling evaluation of myofiber size and distribution. The NMJs appear to include both en plaque and en grappe synapses, while NMJ density is much higher in EOMs than in somatic muscles. In conclusion, zebrafish and human EOM anatomy are generally homologous, supporting the use of zebrafish for studying EOM biology. However, anatomic differences exist, revealing divergent evolutionary pressures.     

The development of extraocular muscle calcium homeostasis parallels visuomotor system maturation

Extraocular muscle is modulated by unique genetic and epigenetic factors to produce an atypical phenotype. As a prelude to regulation studies, we characterized the development of cation homeostasis in the predominately fast-twitch extraocular muscles. By atomic absorption spectroscopy, total muscle calcium content declined from birth to postnatal day 27 and, thereafter, stabilized at a low level in limb but increased dramatically in extraocular muscle (to 40x limb values). By ELISA, the slow isoform of sarcoplasmic reticulum Ca2+-ATPase predominated in neonatal eye muscle, but subsequently was largely replaced by the fast isoform. This replacement in eye muscle was completed later than in limb. Residual, slow Ca2+-ATPase likely resides in an unusual slow tonic fiber type characteristic of eye muscle. Maturation of the definitive extraocular muscle Ca2+-ATPase pattern paralleled myofiber Ca2+ and sarcoplasmic reticulum content. These data show that, like myosin heavy chain expression patterns, the development of cation homeostatic mechanisms in extraocular muscle parallels landmarks in the maturation of vision and eye movement control systems. Findings suggest that cation homeostasis in extraocular muscle may be susceptible to perturbations of the developing visual sensory system, as we have previously shown for myosin.     

Cerebral extraocular photoreceptors in ants

Clusters of dark pigmented cells, called putative cerebral extraocular photoreceptors (CEPs), are described in the optic lobes of four ant species: Atta sexdens, Camponotus rufipes, Camponotus crassus, and Pseudomyrmex adustus. Electron-micrographs of CEPs show a central rhabdom-like structure formed by tightly interleaved cells containing shielding pigments, with axons projecting toward the outer optic chiasm. The presence of a great number of mitochondria, nucleolus, and multivesciular bodies suggests that these clusters might be functional extraocular photoreceptors. Although some branches from GABA-like immunoreactive neurones occur near the CEP region, GABA-immunoreactivity was not detected in CEPs. The ant's cephalic cuticle blocks short wavelengths (< 500 nm) and the light transmittance is less than 20% for wavelengths between 500-700 nm. Ant species with both diurnal and nocturnal habits and heightened nocturnal visual sensitivity (A. sexdens and C. rufipes) contain more CEPs than those with diurnal habits and lower visual sensitivity (C. crassus and P. adustus). The reduction of light reaching this putative extra-ocular system could act as a signal for a circadian pacemaker and, as a possible consequence, lead to an increase of nocturnal visual sensitivity of the compound eyes and/or nocturnal locomotor activity, as already observed in the species studied.     

The sizes of motoneurons supplying hindlimb muscles in the mouse

Motoneurons supplying identified muscle groups in the mouse spinal cord were labelled by retrograde transport of horseradish peroxidase. The size of motoneurons was estimated by measuring perimeter and cross-sectional area at the level of the nucleolus for the following seven major muscle groups: quadriceps femoris, adductors and gracilis, gluteal musculature, hamstring muscles, posterior crural musculature, anterolateral crural musculature and intrinsic musculature of the foot. The qualitative observation of two size ranges of motoneuron was supported by the measurements. Frequency distribution histograms of motoneuronal cross sectional area were bimodal for all motoneuronal groups except for the foot musculature. The population parameters and proportions for the six bimodal histograms were estimated by the method of maximum likelihood. It was found that the mean area of the small neuron component, which were presumed to be gamma motoneurons, was similar for the six bimodal systems. In contrast to this the mean area of the large neuron component, presumed to be alpha motoneurons, was found to be different for the six bimodal systems; motoneurons supplying more proximal muscles showed a larger mean area than those supplying distal muscles. The mean area of both components was unaffected by survival time and this was interpreted as indicating that changes in survival time did not label greater numbers of small or large motoneurons. The proportion of motoneurons in the small neuron component was found to vary from 9 to 27%.     

The ethics of conversion therapy

... Both the past and present have seen a number of methods being used to extinguish homoerotic desire and behavior and to inaugurate heteroeroticism in their place, methods I will here call conversion therapies... The typical defense of such therapy holds that even if homoeroticism is not necessarily a disease or evil, neither is it a universal good... Conversion therapy is morally defensible, on such a view, because some people suffer from the perceived consequences of homoerotic orientations despite the freedom and toleration extended to gay men and lesbians in certain areas... Against the view that conversion therapy is morally defensible as a matter of personal preference, I here argue that such therapy is morally suspect and should be resisted for a number of reasons....