My lab studies the involvement of Hedgehog signaling and homeobox transcription factors in brain development, adult stem cells, and cancer.
The mammalian brain is an extremely complex structure both anatomically and functionally, that simultaneously integrates multiple inputs to produce an appropriate response. Our studies are aimed at bridging the gap between studies of neural development and analysis of the circuitry and function of the adult brain. The embryonic brain region that gives rise to the midbrain (mesencephalon) and anterior hindbrain (rhombomere 1) is an ideal model system for studying the genetic pathways that regulate the continuum of brain development and function. Anterior-posterior patterning of the mesencephalon and rhombomere 1 is orchestrated by an organizing center in the isthmus located between the two regions, whereas dorsal-ventral patterning is determined by Sonic hedgehog (Shh) expressed by the ventral floorplate. Fgf8 is the key isthmic organizer molecule, and acts by regulating the expression of genes such as Engrailed1 and 2.
One focus of our research is to determine how the mesencephalon and rhombomere 1, which gives rise to the cerebellum, are patterned in three dimensions over time. A second research focus is how the Engrailed genes regulate development of the cerebellum, a brain structure with a striking morphology consisting of folia separated by fissures of varying lengths. Underlying the folia, is a complex array of molecular codes consisting of parasagittal stripes of gene expression. Since the conserved pattern of folia and gene expression domains in mammals likely serves as a platform for organizing the sensory-motor circuits of the cerebellum, it is important to understand how such complex morphology and molecular coding arise. Our third area of research is understanding the degree to which resident stem cells in the adult brain, and other organs, can replenish damaged tissue or contribute to cancers. We are studying how the Shh signaling pathway regulates the behavior of adult stem cells through modifying the activity of the Gli transcription factors.
The Joyner laboratory studies mammalian brain development and the biology of adult stem cells using mouse as a model organism. Developmental mutants and alleles to mark and follow cells are created using sophisticated genetic approaches to study the ultimate function of genes in vivo and the fate of cells as they develop. These approaches are complemented by short term in vitro brain explant assays and electroporation experiments in chick embryos to rapidly compare the function of different proteins. Our three general areas of research are:
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Sillitoe, R.V., Vogel, M.W., Joyner, A.L. (2010) Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map. J. Neuroscience, 30: 10015-10024.
Brownell, I., Guevara, E., Loomis, C.A., Joyner, A.L. (2011) Nerve-derived Sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal skin stem cells. Cell Stem Cell. 8: 552-565.
Lao, Z., Raju, P., Bai, B and Joyner, A.L. (2012) MASTR: a technique for mosaic mutant analysis with spatial and temporal control of recombination using conditional floxed alleles in mice. Cell Reports, 2: 386-396.
Petrova, R., Garcia, A.D.R., Joyner, A.L. (2013) Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions. J Neuroscience, 33:17490-17505.
Peng, Y.-C., Levine, C.M., Zahid, S., Wilson, E.L., Joyner, A.L. (2013) Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration. PNAS, 110:20611-20616.
Alexandra Joyner, a global leader in mouse developmental genetics, studies how the body’s natural stem cells might be harnessed to fight disease.