Lab
Chandrasekhar Lab
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Statement of Research Interest
Neuronal Migration in the Vertebrate Brain
The long-term goal of our research is to understand the mechanisms that mediate neuronal migration in mammals. In the vertebrate embryo, neurons frequently migrate long distances to reach their final positions, where they assemble into complex networks that control physiology and behavior. Many human neurological disorders result when neurons either migrate aberrantly or fail to migrate. Therefore, it is essential to understand the mechanisms mediating migration of specific neuronal types, so that the causes of and potential remedies for human brain disorders can eventually be identified. Our studies may also impact efforts to induce stem cell-derived neurons to migrate accurately into brain regions damaged by injury or disease.
Our lab employs the migration of facial branchiomotor neurons (FBMNs) in the zebrafish and mouse hindbrain as a model for neuronal migrations in mammals. The FBMNs are a subset of cranial motor neurons found in the vertebrate brainstem. In mammals, the FBMNs compose the motor component of cranial nerve VII, and innervate muscles of facial expression, and of the middle ear and upper neck.
Currently, our work is focused on elucidating the roles of components of the Wnt/Planar Cell Polarity pathway in regulating the directionality and extent of FBMN migration. These studies are performed in zebrafish and mice, using experimental approaches that each model system is uniquely suited for, such as time-lapse imaging and conditional gene knockout.
We showed previously that tangential migration of facial branchiomotor neurons (FBMNs) is completely eliminated in the zebrafish gastrulation mutant trilobite. The trilobite locus encodes Vangl2, a four-pass transmembrane protein that is a component of the non-canonical Wnt/Planar Cell Polarity (Wnt/PCP) pathway. Vangl2 is expressed in FBMNs and surrounding tissues during the period of FBMN migration. Three major lines of investigation in the lab are:
Structure-function analysis of zebrafish Vangl2 protein (Dr. Pan)
While the C-terminal cytoplasmic region of Vangl2 is necessary for mediating gastrulation-associated movements, the roles of the N-terminal cytoplasmic region and of the extracellular loops have not been examined. We are generating transgenic lines expressing variant forms of the Vangl2 protein to test their abilities to rescue the FBMN migration defect of trilobite mutants. These studies will define the regions of Vangl2 (and the molecular interactions they participate in) involved in neuronal migration.
Cellular site of Vangl2 function (Dr. Sittaramane)
We showed previously that vangl2 functions non-cell autonomously (i.e., outside motor neurons) for FBMN migration. We are performing targeted cell transplants to examine whether vangl2 functions in specific cell types such as mesoderm and floorplate to regulate FBMN migration.
Role of Wnt/PCP genes in FBMN migration in mice (Mr. Glasco)
Our zebrafish work and other studies have shown that non-canonical Wnt/PCP pathway components play essential roles in mediating FBMN migration. Furthermore, many of these molecules function non-cell autonomously to regulate FBMN migration, suggesting that novel signaling mechanisms may be involved. We are examining the extent to which these functions are evolutionarily conserved by testing whether these molecules also have essential functions during FBMN migration in mammals (i.e., mice).
Other Projects:
- Analysis of the role of integrin signaling in FBMN migration.
- Reverse genetic screen for genes regulating neuronal development in the zebrafish hindbrain.
- Analysis of roles of the Gbx transcription factors in motor neuron development.
- Establishment of an in vitro (cell culture) system using human cancer cells to study the roles of Wnt/PCP components in migration.
- Analysis of the effects of endocrine disruptors on zebrafish development.
The long-term goal of our research is to understand the mechanisms that mediate neuronal migration in mammals. In the vertebrate embryo, neurons frequently migrate long distances to reach their final positions, where they assemble into complex networks that control physiology and behavior. Many human neurological disorders result when neurons either migrate aberrantly or fail to migrate. Therefore, it is essential to understand the mechanisms mediating migration of specific neuronal types, so that the causes of and potential remedies for human brain disorders can eventually be identified. Our studies may also impact efforts to induce stem cell-derived neurons to migrate accurately into brain regions damaged by injury or disease.
Our lab employs the migration of facial branchiomotor neurons (FBMNs) in the zebrafish and mouse hindbrain as a model for neuronal migrations in mammals. The FBMNs are a subset of cranial motor neurons found in the vertebrate brainstem. In mammals, the FBMNs compose the motor component of cranial nerve VII, and innervate muscles of facial expression, and of the middle ear and upper neck.
Currently, our work is focused on elucidating the roles of components of the Wnt/Planar Cell Polarity pathway in regulating the directionality and extent of FBMN migration. These studies are performed in zebrafish and mice, using experimental approaches that each model system is uniquely suited for, such as time-lapse imaging and conditional gene knockout.
We showed previously that tangential migration of facial branchiomotor neurons (FBMNs) is completely eliminated in the zebrafish gastrulation mutant trilobite. The trilobite locus encodes Vangl2, a four-pass transmembrane protein that is a component of the non-canonical Wnt/Planar Cell Polarity (Wnt/PCP) pathway. Vangl2 is expressed in FBMNs and surrounding tissues during the period of FBMN migration. Three major lines of investigation in the lab are:
Structure-function analysis of zebrafish Vangl2 protein (Dr. Pan)
While the C-terminal cytoplasmic region of Vangl2 is necessary for mediating gastrulation-associated movements, the roles of the N-terminal cytoplasmic region and of the extracellular loops have not been examined. We are generating transgenic lines expressing variant forms of the Vangl2 protein to test their abilities to rescue the FBMN migration defect of trilobite mutants. These studies will define the regions of Vangl2 (and the molecular interactions they participate in) involved in neuronal migration.
Cellular site of Vangl2 function (Dr. Sittaramane)
We showed previously that vangl2 functions non-cell autonomously (i.e., outside motor neurons) for FBMN migration. We are performing targeted cell transplants to examine whether vangl2 functions in specific cell types such as mesoderm and floorplate to regulate FBMN migration.
Role of Wnt/PCP genes in FBMN migration in mice (Mr. Glasco)
Our zebrafish work and other studies have shown that non-canonical Wnt/PCP pathway components play essential roles in mediating FBMN migration. Furthermore, many of these molecules function non-cell autonomously to regulate FBMN migration, suggesting that novel signaling mechanisms may be involved. We are examining the extent to which these functions are evolutionarily conserved by testing whether these molecules also have essential functions during FBMN migration in mammals (i.e., mice).
Other Projects:
- Analysis of the role of integrin signaling in FBMN migration.
- Reverse genetic screen for genes regulating neuronal development in the zebrafish hindbrain.
- Analysis of roles of the Gbx transcription factors in motor neuron development.
- Establishment of an in vitro (cell culture) system using human cancer cells to study the roles of Wnt/PCP components in migration.
- Analysis of the effects of endocrine disruptors on zebrafish development.
Lab Members
| Pan, Xiufang Post-Doc | Sittaramane, Vinoth Post-Doc | Baccam, Chiengkham Fish Facility Staff |