My research focuses on understanding how appropriate connectivity within the nervous system is established during development. My research examines this process both in health and disease, with a focus on Down syndrome. I am interested in the mechanisms by which growth cones, which are the pathfinding structures of the developing neuron, migrate to and connect with their appropriate targets. My research employs a wide variety of molecular, cellular and advanced imaging techniques, including primary cell culture, viral-mediated gene expression, innovative fluorescent proteins and reporters, live cell imaging and TIRF microscopy, to elucidate the mechanisms underlying neural development. Proximately, the objective of my research is to understand how growth cone behavior is affected by external cues, as well as the intracellular molecular mechanisms that are activated by these cues. Ultimately, studying these mechanisms will allow us to understand how the early establishment of key neural circuits leads to the appropriate expression of adult cognition and behavior, as well as provide insight into treatments for neurodevelopmental disorders.
There are two major facets to my research program: (1) the neurodevelopmental basis of Down syndrome and (2) the molecular mechanisms regulating local translation of mRNAs during axon guidance.
Neurodevelopmental Basis of Down syndrome.
Down syndrome affects approximately 1 in every 700 infants, and is a major cause of a number of birth defects, including intellectual disability. Down syndrome results from the trisomy of human chromosome 21. However, hundreds of genes are located on this chromosome, and much is still unknown about the specific genes and molecular mechanisms contributing to the pathology of Down syndrome. Using both mouse and human models of Down syndrome, we investigate the molecular mechanisms underlying Down syndrome and how this contributes to the formation of inappropriate nervous system connectivity.
Molecular mechanisms regulating local translation of mRNAs during axon guidance.
The other major focus in our lab examines the basic mechanisms underlying the transport and local translation of mRNAs in developing axons. Recently it has become evident that the local translation of select mRNA transcripts within the growth cone itself is necessary for cue-mediated axon growth and guidance. However, our understanding of which mRNAs contribute to appropriate axon guidance and the mechanisms underlying their translation is extremely limited. Research in my lab focuses on understanding the molecular and cellular mechanisms underlying local translation in growth cones, and how this regulates appropriate wiring of the developing nervous system.
- Kershner L. and Welshhans K. (2017) RACK1 regulates neural development. Neural Regeneration Research. 12(7): 1036-1039.
- Kershner L. and Welshhans K. (2017) RACK1 is necessary for the formation of point contacts and regulates axon growth. Developmental Neurobiology. doi: 10.1002/dneu.22491.
- Lepelletier L., Langlois S.D., Kent C.B., Welshhans K., Morin S., Bassell G.J., Yam P.T., Charron F. (2017) Sonic Hedgehog guides axons via Zipcode Binding Protein 1-mediated local translation. Journal of Neuroscience. 37(7): 1685-1695.
- Jain S. and Welshhans K. (2016) Local translation of cell adhesion molecules in axons. Neural Regeneration Research. 11(4): 543-544.
- Jain S. and Welshhans K. (2016) Netrin-1 induces local translation of Down syndrome cell adhesion molecule in axonal growth cones. Developmental Neurobiology. 76(7): 799-816.
- Ceci M., Welshhans K., Ciotti M.T., Brandi R., Parisi C., Paoletti F., Pistillo L., Bassell G., Cattaneo A. (2012) RACK1 is a ribosome scaffold protein for β-actin mRNA/ZBP1 complex. PLoS ONE. 7(4): e35034.
- Welshhans K. and Bassell G.J. (2011) Netrin-1-induced local β-actin synthesis and growth cone guidance requires zipcode binding protein 1. Journal of Neuroscience. 31: 9800-9813.
- Sasaki Y., Welshhans K., Wen Z., Yao J., Xu M., Goshima Y., Zheng J.Q., and Bassell G.J. (2010) Phosphorylation of zipcode binding protein 1 is required for brain-derived neurotrophic factor signaling of local β-actin synthesis and growth cone turning. Jo
- Zou J., Hofer A.M., Lurtz M.M., Gadda G., Ellis A.L.,Chen N., Huang Y., Holder A., Ye Y., Louis C.F., Welshhans K., Rehder V., and Yang J.J. (2007) Developing sensors for real-time measurement of high Ca2+ concentrations. Biochemistry. 46: 12275-12288.
- Welshhans K. and Rehder V. (2007) Nitric oxide regulates growth cone filopodial dynamics via ryanodine receptor-mediated calcium release. European Journal of Neuroscience. 26(6): 1537-47.
- Tornieri K., Welshhans K., Geddis M.S., and Rehder, V. (2006) Control of neurite outgrowth and growth cone motility by phosphatidylinositol-3-kinase. Cell Motility and the Cytoskeleton. 63(4): 173-92.
- Welshhans K. and Rehder V. (2005) Local activation of the nitric oxide/cyclic guanosine monophosphate pathway in growth cones regulates filopodial length via protein kinase G, cyclic ADP ribose, and intracellular Ca2+ release. European Journal of Neurosc
- Zou J., Ye Y., Welshhans K., Lurtz M., Ellis A., Louis C., Rehder V., and Yang J.J. (2005) Expression and optical properties of green fluorescent protein expressed in different cellular environments. Journal of Biotechnology. 119(4): 368-378.
- Lynn-Bullock C.P., Welshhans K., Pallas S.L., and Katz P.S. (2004) The effect of oral 5-HTP administration on 5-HTP and 5-HT immunoreactivity in monoaminergic brain regions of rats. Journal of Chemical Neuroanatomy. 27(2):129-38.