The Molecular Neurobiology of Breathing
Lead Research Organisation:
King's College London
Department Name: MRC Ctr for Developmental Neurobiology
Abstract
Most ?higher? animals that live on land, including humans, breathe air through lungs. The expansion and
contraction of the lungs during breathing(respiration) is driven by a group of muscles that are attached to the rib cage. The breathing rhythm itself is generated in the brain and then conveyed to the muscles through a specialized type of nerve cell called respiratory motor neuron . I propose to investigate the genetic program that instructs some embryonic cells to become respiratory motor neurons prior to birth. Such a program typically consists of two sets of molecules: One set controls when and where genes are active within the body, and it defines the identity of the cells. A second set of molecules, regulated by the first one, allows developing motor neurons to connect to their ?right? target muscle. The genetic elements that constitute the ?respiratory motor neuron? program and their logical relationships to each other are currently
not known. Once I have decoded the program, I may be able to artificially create new nerve cells of this
type from embryonic stem cells and use them to replace dead or disconnected ones. Such a therapeutic
approach could restore the ability to breathe in patients suffering from neuromuscular disease or spinal cord injury.
contraction of the lungs during breathing(respiration) is driven by a group of muscles that are attached to the rib cage. The breathing rhythm itself is generated in the brain and then conveyed to the muscles through a specialized type of nerve cell called respiratory motor neuron . I propose to investigate the genetic program that instructs some embryonic cells to become respiratory motor neurons prior to birth. Such a program typically consists of two sets of molecules: One set controls when and where genes are active within the body, and it defines the identity of the cells. A second set of molecules, regulated by the first one, allows developing motor neurons to connect to their ?right? target muscle. The genetic elements that constitute the ?respiratory motor neuron? program and their logical relationships to each other are currently
not known. Once I have decoded the program, I may be able to artificially create new nerve cells of this
type from embryonic stem cells and use them to replace dead or disconnected ones. Such a therapeutic
approach could restore the ability to breathe in patients suffering from neuromuscular disease or spinal cord injury.
Technical Summary
All land vertebrates, including humans, use lungs to breathe air. The inspiratory and expiratory movements
of the lungs are driven by a complex neural circuitry that consists of a central network in the brainstem that generates breathing rhythms and an output layer of motor neurons which connect to respiratory muscles.
These respiratory circuits develop prenatally and have to become functional immediately after birth. While significant progress has been made in understanding the central pattern generator itself, very little is known about the formation of neural circuits that turn breathing rhythms into coordinated motor output. Here, I propose several experimental approaches to address how respiratory motor neurons are specified and connect to the appropriate target muscles. Using a combination of in vitro differentiation of motor neurons from mouse ES cells, mouse genetics, imaging and systematic analysis of gene expression, I aim at defining the transcriptional program of respiratory motor neuron identity. More generally, this study should also provide insights into the crucial, but still largely unresolved, question of how neurons acquire their individual identities.
of the lungs are driven by a complex neural circuitry that consists of a central network in the brainstem that generates breathing rhythms and an output layer of motor neurons which connect to respiratory muscles.
These respiratory circuits develop prenatally and have to become functional immediately after birth. While significant progress has been made in understanding the central pattern generator itself, very little is known about the formation of neural circuits that turn breathing rhythms into coordinated motor output. Here, I propose several experimental approaches to address how respiratory motor neurons are specified and connect to the appropriate target muscles. Using a combination of in vitro differentiation of motor neurons from mouse ES cells, mouse genetics, imaging and systematic analysis of gene expression, I aim at defining the transcriptional program of respiratory motor neuron identity. More generally, this study should also provide insights into the crucial, but still largely unresolved, question of how neurons acquire their individual identities.
