Noelle Dwyer

Education

  • BA, Rice University
  • PhD, University of California, San Francisco
  • Postdoc, The Salk Institute
  • Postdoc, Beth Israel Hospital, Boston, MA

Primary Appointment

  • Associate Professor, Cell Biology

Contact

Research Interest(s)

Neural Development; Cell Division in Neural Stem Cells; Axon Outgrowth and Guidance

Research Description

Development of the Cerebral Cortex

Your cerebral cortex mediates your conscious sensory perceptions, thoughts, and behaviors. To perform these functions, the cortex must develop the proper structure and circuitry during early life. Our lab works to help understand this process, and the disruptions that cause neurodevelopmental disorders.

In the embryo, the cortex begins as an epithelial sheet of neural stem cells. The sheet expands and balloons outward due to symmetric divisions of these polarized cells. Later, the stem cells divide asymmetrically, eventually generating billions of neurons and glia. The neurons and glia form a six-layered structure with different areas specialized for functions such as vision or hearing. Finally, neurons within each area must be "wired" to other specific brain regions through axonal connections. The genetic and cellular mechanisms that control all these events are only beginning to be understood, and comprise some of the most compelling mysteries of biology and medicine. How is the correct size of the cerebral cortex specified? What gives the human cortex abilities that are unique among animals? What are the changes in neural development that underlie brain malformations, seizures, intellectual disability, schizophrenia, or autism?

The long-term goal of our lab is to help answer these questions, and elucidate fundamental cellular mechanisms important not only in the nervous system, but in development of many tissues and disease processes. In particular, we have been using forward genetics in mice to identify novel genes involved in cortical development. We isolated several mutants with specific defects in brain growth and wiring. By identifying the mutated genes and studying the cellular roles of the encoded proteins, with both in vivo and in vitro experiments, we hope to understand how mutations in single genes can cause changes in brain structure. Our novel gene discoveries have led to studies on protein localization, the cytoskeleton, and cell shape changes, within neurons, progenitor cells, and other cell types.

Axon outgrowth and guidance: how the brain is wired together One of the mutants we isolated, called baffled, has strong defects in axon outgrowth and guidance. Axonal connections between the cortex and thalamus are delayed in their growth, especially at a critical boundary crossing. In addition, the axons are disorganized and overfasciculated (stuck together). Cortical neurons dissociated from baffled mutant brains have shorter axons in culture. By genetic mapping and cloning, we found that baffled carries a mutation in the endoplasmic reticulum (ER) chaperone protein BiP/GRP78. BiP has a well-known function in protecting aging neurons against neurodegeneration, but its roles in developing neurons had not been well studied. Our findings add to accumulating evidence suggesting that axon outgrowth and guidance are particularly vulnerable to deficits in ER functions.

Neurogenesis: how cell division mechanisms produce different daughter cells at different times to build a proper brain

The highly polarized structure of neuroepithelial stem cells places special constraints on cell division. The cell cycle, mitosis, and cytokinesis must be coordinated with nuclear migration and the proper timing of neuron production. Furthermore, the cells must split in half while maintaining their polarity and attachments within the epithelial sheet. We are studying the mechanisms of these unusual cell divisions, how the mechanisms differ between symmetric and asymmetric division, and how they may influence fates of the daughter cells. By elucidating mechanisms of cell division in neural epithelium, we can help to understand how other epithelial tissues grow, how they may repair themselves after damage, or how errors in division lead to tumor formation.

The magoo mutant has a small brain due to a mutation in a cytoskeletal protein. The role of this protein is not well understood, but it has been shown to be involved in cell division, and overexpressed in some cancers. We are currently studying what goes wrong in neural stem cells and other cells depleted of this protein. This small-brained mutant will help elucidate how the brain is built, and the causes of human brain malformations.

Selected Publications

  • Janisch K, Vock V, Fleming M, Shrestha A, Grimsley-Myers C, Rasoul B, Neale S, Cupp T, Kinchen J, Liem K, Dwyer N. The vertebrate-specific Kinesin-6, Kif20b, is required for normal cytokinesis of polarized cortical stem cells and cerebral cortex size. Development (Cambridge, England). 2013;140(23): 4672-4682. PMID: 24173802
  • Favero C, Henshaw R, Grimsley-Myers C, Shrestha A, Beier D, Dwyer N. Mutation of the BiP/GRP78 gene causes axon outgrowth and fasciculation defects in the thalamocortical connections of the mammalian forebrain. The Journal of comparative neurology. 2012. PMID: 22821687 | PMCID: NIHMS395723
  • Dwyer N, Manning D, Moran J, Mudbhary R, Fleming M, Favero C, Vock V, O'Leary D, Walsh C, Beier D. A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype. Neural development. 2011;6 3. PMID: 21214893 | PMCID: PMC3024922
  • Dwyer N, Winckler B. TGF-beta receptors PAR-ticipate in axon formation. Cell. 2010;142(1): 21-3. PMID: 20603011
  • Smits P, Bolton A, Funari V, Hong M, Boyden E, Lu L, Manning D, Dwyer N, Moran J, Prysak M, Merriman B, Nelson S, Bonafé L, Superti-Furga A, Ikegawa S, Krakow D, Cohn D, Kirchhausen T, Warman M, Beier D. Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. The New England journal of medicine. 2010;362(3): 206-16. PMID: 20089971 | PMCID: PMC3108191
  • Moran J, Bolton A, Tran P, Brown A, Dwyer N, Manning D, Bjork B, Li C, Montgomery K, Siepka S, Vitaterna M, Takahashi J, Wiltshire T, Kwiatkowski D, Kucherlapati R, Beier D. Utilization of a whole genome SNP panel for efficient genetic mapping in the mouse. Genome research. 2006;16(3): 436-40. PMID: 16461637 | PMCID: PMC1415208
  • Dwyer N, Adler C, Crump J, L'Etoile N, Bargmann C. Polarized dendritic transport and the AP-1 mu1 clathrin adaptor UNC-101 localize odorant receptors to olfactory cilia. Neuron. 2001;31(2): 277-87. PMID: 11502258
  • Dwyer N, O'Leary D. Tbr1 conducts the orchestration of early cortical development. Neuron. 2001;29(2): 309-11. PMID: 11239419
  • Liu Q, Dwyer N, O'Leary D. Differential expression of COUP-TFI, CHL1, and two novel genes in developing neocortex identified by differential display PCR. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000;20(20): 7682-90. PMID: 11027229
  • Signor D, Wedaman K, Orozco J, Dwyer N, Bargmann C, Rose L, Scholey J. Role of a class DHC1b dynein in retrograde transport of IFT motors and IFT raft particles along cilia, but not dendrites, in chemosensory neurons of living Caenorhabditis elegans. The Journal of cell biology. 1999;147(3): 519-30. PMID: 10545497 | PMCID: PMC2151193
  • Dwyer N, Troemel E, Sengupta P, Bargmann C. Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein. Cell. 1998;93(3): 455-66. PMID: 9590179
  • Chou J, Troemel E, Sengupta P, Colbert H, Tong L, Tobin D, Roayaie K, Crump J, Dwyer N, Bargmann C. Olfactory recognition and discrimination in Caenorhabditis elegans. Cold Spring Harbor symposia on quantitative biology. 1996;61 157-64. PMID: 9246444
  • Troemel E, Chou J, Dwyer N, Colbert H, Bargmann C. Divergent seven transmembrane receptors are candidate chemosensory receptors in C. elegans. Cell. 1995;83(2): 207-18. PMID: 7585938
  • Brewster J, de Valoir T, Dwyer N, Winter E, Gustin M. An osmosensing signal transduction pathway in yeast. Science (New York, N.Y.). 1993;259(5102): 1760-3. PMID: 7681220
  • Sengupta P, Colbert H, Kimmel B, Dwyer N, Bargmann C. The cellular and genetic basis of olfactory responses in Caenorhabditis elegans. Ciba Foundation symposium. 1993;179 235-44; discussion 244-50. PMID: 8168378