1986 — 1991 |
Landis, Story C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Studies of Synapse Formation @ Case Western Reserve University
During development, neurons make a number of important decisions and the normal function of the mature organism depends upon the correctness of these decisions. One such decision is which neurotransmitter(s) to use. The developmental mechanisms which control this choice and allow for correct matching of transmitter and target are poorly understood in the periphery and undefined in the central nervous system. The cholinergic sympathetic neurons that innervate sweat glands undergo a transition from adrenergic to cholinergic function during normal development in the intact animal similar to that previously described in sympathetic neurons developing in culture when exposed to a soluble factor released from heart cells. We propose to obtain direct evidence for a transition in transmitter phenotype using immunocytochemical techniques and to determine whether other cholinergic sympathetic and cranial parasympathetic neurons undergo such a change during normal development. Using in vitro and in vivo manipulations, we will determine whether the change in neurotransmitter phenotype documented for the sweat gland innervation is induced by their target and will determine the effect of the change of the expression of transmitter receptors on the target cells. Finally, we will examine early embryonic sympathetic ganglia to determine whether small intensely fluorescent or SIF cells are the common multipotential precursor for the sympathoadrenal lineage including adrenergic and cholinergic sympathetic neurons, mature SIF cells and adrenal medullary cells. The long-term goal of these studies is to understand the normal developmental decisions and the mechanisms that underlie them that shape the formation of functionally appropriate synapses in the nervous system.
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0.906 |
1988 — 1992 |
Landis, Story C. |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Developmental Neurology @ Case Western Reserve University |
0.906 |
1989 — 1995 |
Landis, Story C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Developmental Regulation of Neuropeptide Expression @ Case Western Reserve University
The long term goal of the research proposed in this application is to understand the mechanisms that underlie the formation of functionally appropriate synaptic connections during development of the nervous system. An important aspect of this process is the determination of the neurotransmitter phenotype of individual neurons. Recently, neuroscientists have recognized that many neurons contain a neuropeptide(s) in addition to a classical neurotransmitter. Neuropeptides have been shown to function as neuro-transmitters or neuromodulators in the adult and some evidence suggests that they may play important roles in development as well. These findings raise the obvious questions of when neuropeptides appear during development and what factors influence the neuropeptide(s) a neuron will express. Preliminary data obtained in studies of rat sympathetic neurons developing in vivo suggest that some neuropeptides appear very early, that individual neurons transiently express multiple neuropeptides, and that experimental manipulation during development can alter peptide phenotype in a striking fashion. Further, we have evidence that peptide function in a class of neurons, parasympathetic ciliary neurons, can be controlled post-translationally. Using immunocytochemidstry and in situ hybridization, we will determine when neuropeptides and the mRNAs that encode them are first expressed in developing sympathetic cells and whether changes in expression occur. By interfering with normal neuron-target interactions, we will examine plasticity of neuropeptide expression and study how peptidergic phenotypes are established in vivo. Finally, we will study the development of processing of one neuropeptide, Neuropeptide Y, in sympathetic neurons and the possible role that processing, packaging and/or transport may play in regulating its function. This latter will be accomplished by using rat ciliary neurons, cells in which these functions can be altered experimentally. The studies proposed will provide important new information concerning the development of neuropeptide expression, processing and transport. They may elucidate the pathogenesis of developmental disorders of the nervous system and of neurodegenerative disease involving peptide dysfunction.
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0.906 |
1992 — 1994 |
Landis, Story C. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synapse Formation @ Case Western Reserve University
The long-term goal of the proposed research is to understand how functionally appropriate synapses are established during development. The aspects of synapse formation to be examined are how neurons acquire their repertoire of neurotransmitters and how target tissues acquire their complement of transmitter receptors and effector proteins. These questions will be addressed in the sympathetic nervous system because (1) the transmitters and receptors are well characterized and tools exist to study them, (2) culture techniques permit dissection of mechanism in a reduced system and (3) development which occurs postnatally is accessible to manipulation in vivo. Previous studies revealed that during normal development, a population of sympathetic neurons changes their transmitter phenotype, from noradrenergic to cholinergic. This switch is retrogradely specified by a soluble factor(s) produced by their target tissue, sweat glands. While innervation is not required for sweat glands to express muscarinic receptors, the appearance of cholinergic function in sweat gland neurons is required for the glands to develop secretory responsiveness. We now plan to determine whether sympathetic neurons, in addition to those that innervate sweat glands, undergo a transmitter switch and if so whether the target induces it. The role of target tissues in determining neuronal phenotype will be examined in several other paradigms. Tabby mutant mice lacking sweat glands will be used to determine if target tissues are required to guide sympathetic axons. Mice in which the CDF/LIF gene has been "knocked out" will be studied to establish whether CDF/LIF plays a role in the transmitter switch of sweat gland neurons. Transplantation experiments will be used to determine whether sympathetic target tissues transneuronally specify the neuropeptide content of their preganglionic innervation. Retrograde tracing will be combined with axotomy to assess the stability of target-specified transmitter properties in sweat gland neurons. We will also determine which aspects of target tissue development are regulated by innervation. Preliminary evidence suggests that innervation regulates cholinergic differentiation factor production by sweat glands. We will ascertain whether catecholamines are responsible. Other receptors in sweat glands will be examined to determine if their expression is controlled by innervation. The expression of candidate effector proteins required for responsiveness and regulated by cholinergic innervation will be studied. Finally, we will determine whether a critical period exists for target-induced changes in transmitter properties. These studies will elucidate the cellular and molecular mechanisms responsible for normal synaptogenesis and provide insight into where this process may be disrupted during abnormal development.
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0.906 |
1993 — 1994 |
Landis, Story C. |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Developmental Neurology Training Grant @ Case Western Reserve University |
0.906 |