Robert F. Hevner, MD, PhD is a Professor of Neurological Surgery and Pathology. He is a member of the new Seattle Children’s Hospital Center for Neuroscience. His research focuses on genetic mechanisms of brain development, with particular interest in relation between embryonic and adult neurogenesis in transcription factor expression. He is National Institutes of Health (NIH) grant supported.
Dr. Hevner's research group studies transcription factors and neurogenesis in the developing and adult mouse brain. Transcription factors are master regulators of gene expression that act together, in combination and sequentially, to activate or repress genetic programs of cell cycle progression, cell migration, axon guidance, synapse formation, and neuronal fate and subtype specification.
These fundamental programs in neurogenesis hold great scientific and medical interest, because of their significance for human brain development and disease. When all goes well, these developmental programs produce the extraordinary structural and functional complexity of the human brain and mind. But when development goes awry, for example, due to a genetic mutation, defects of these programs cause neuropsychiatric disorders - such as autism, epilepsy and mental retardation - often with devastating consequences for individuals, families and society. These human disorders are an important part of Dr. Hevner's clinical focus in pediatric and developmental neuropathology, and so his research and clinical work complement each other. As an independent faculty investigator, Dr. Hevner has followed the strands of transcription factors and neurogenesis into four main areas:
cerebral cortex development
Dr. Hevner's goals in future studies are to understand the pathogenesis of pediatric brain diseases, and to develop new therapeutic approaches based on neuroregeneration.
How do the layer–specific properties of cortical projection neurons develop?
Previous studies have shown that, with few exceptions, cells in deeper layers of cortex (the subplate and layer 6 are the deepest) are "born" earlier in embryonic development than are cells in superficial layers (layer 1 is most superficial). The "birthdate" of a neuron is defined as the day in development when the cell undergoes its last mitotic division, and makes the shift from proliferating progenitor to postmitotic neuron. In general, the cells in each layer share similar properties such as their connections and molecular expression. Thus, layer-specific properties are highly correlated with cell birthdate in the cortex. This correlation, and other evidence have led to the hypothesis that laminar fate is specified by birthdate.
Is birthdate the only factor that specifies laminar fate, or are other mechanisms at work? The answers to this question are important, because disorders of cortical development may involve errors of laminar fate specification. Moreover, if we can learn to control aspects of laminar fate specification in neurons—for example, specification of axonal projection targets—we might be able to direct the regeneration of the nervous system, perhaps using engineered stem cells. We are addressing this question by studying mice with mutations that disturb laminar fate specification.
How does the cerebral cortex establish connections with other brain regions—especially the thalamus and the spinal cord?
One of the major challenges in neuroscience today is to understand how the wiring diagram of the brain develops. For example, as shown in the illustration, how do axons (pink) from the cortex (ctx) "know" to grow into the internal capsule (ic), and from there into the dorsal thalamus (dt)? The initial steps in this process appear to be driven by a genetic program, which sets up the overall organization of connections.
In later steps, the connections are further refined by experience– or activity–dependent mechanisms. We are researching the early (embryonic) steps in cortical axon guidance, using a combination of in vitro studies (explant co–culture of cortex and thalamus) and gene expression analysis by microarray hybridization. We have previously found that mice with certain genetic mutations lack connections between the cortex and the thalamus, or between the cortex and the spinal cord. By studying what goes wrong in these mice, we hope to identify the molecules and understand the mechanisms that integrate the cortical circuitry with that of other processing centers.
A great variety of developmentally regulated transcription factor genes are expressed in distinct compartments of the developing brain. For example, Tbr1 and Tbr2 are transcription factors expressed in the developing cortex. Dr. Hevner's research aims to elucidate the role of these genes in normal brain development, and their possible involvement in human neuropsychiatric diseases.
Histology, Immunohistochemistry, and In Situ Hybridization
In vitro transcription (riboprobe)
In situ hybridization
Genotyping, DNA Purification, and PCR
Extraction of tail DNA
DNA Minipreps (QIA spin)
Cell and Tissue Culture
Cortical cell co-culture
Forebrain slice culture
- Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RA, Beyer RP, Bammler TK, Rubenstein JL, Hevner RF. Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13129-34. Epub 2010 Jul 6. PMID: 20615956 [PubMed - indexed for MEDLINE]
- Autism susceptibility candidate 2 (Auts2) encodes a nuclear protein expressed in developing brain regions implicated in autism neuropathology. Bedogni F, Hodge RD, Nelson BR, Frederick EA, Shiba N, Daza RA, Hevner RF. Gene Expr Patterns. 2010 Jan;10(1):9-15. Epub 2009 Dec 3. PMID: 19948250 [PubMed - indexed for MEDLINE]
- Intermediate neuronal progenitors (basal progenitors) produce pyramidal-projection neurons for all layers of cerebral cortex. Kowalczyk T, Pontious A, Englund C, Daza RA, Bedogni F, Hodge R, Attardo A, Bell C, Huttner WB, Hevner RF. Cereb Cortex. 2009 Oct;19(10):2439-50. Epub 2009 Jan 23. PMID: 19168665 [PubMed - indexed for MEDLINE]
- Intermediate progenitors in adult hippocampal neurogenesis: Tbr2 expression and coordinate regulation of neuronal output. Hodge RD, Kowalczyk TD, Wolf SA, Encinas JM, Rippey C, Enikolopov G, Kempermann G, Hevner RF. J Neurosci. 2008 Apr 2;28(14):3707-17. PMID: 18385329 [PubMed - indexed for MEDLINE]
- Role of intermediate progenitor cells in cerebral cortex development. Pontious A, Kowalczyk T, Englund C, Hevner RF. Dev Neurosci. 2008;30(1-3):24-32. Review. PMID: 18075251 [PubMed - indexed for MEDLINE]
- Layer-specific markers as probes for neuron type identity in human neocortex and malformations of cortical development. Hevner RF. J Neuropathol Exp Neurol. 2007 Feb;66(2):101-9. Review. PMID: 17278994 [PubMed - indexed for MEDLINE]
- Unipolar brush cells of the cerebellum are produced in the rhombic lip and migrate through developing white matter. Englund C, Kowalczyk T, Daza RA, Dagan A, Lau C, Rose MF, Hevner RF. J Neurosci. 2006 Sep 6;26(36):9184-95. PMID: 16957075 [PubMed - indexed for MEDLINE]
- Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Hevner RF, Hodge RD, Daza RA, Englund C. Neurosci Res. 2006 Jul;55(3):223-33. Epub 2006 Apr 18. Review. PMID: 16621079 [PubMed - indexed for MEDLINE]
- Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. Fink AJ, Englund C, Daza RA, Pham D, Lau C, Nivison M, Kowalczyk T, Hevner RF. J Neurosci. 2006 Mar 15;26(11):3066-76. PMID: 16540585 [PubMed - indexed for MEDLINE]
- Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, Kowalczyk T, Hevner RF. J Neurosci. 2005 Jan 5;25(1):247-51. PMID: 15634788 [PubMed - indexed for MEDLINE]
- Postnatal shifts of interneuron position in the neocortex of normal and reeler mice: evidence for inward radial migration. Hevner RF, Daza RA, Englund C, Kohtz J, Fink A. Neuroscience. 2004;124(3):605-18. PMID: 14980731 [PubMed - indexed for MEDLINE]
- Beyond laminar fate: toward a molecular classification of cortical projection/pyramidal neurons. Hevner RF, Daza RA, Rubenstein JL, Stunnenberg H, Olavarria JF, Englund C. Dev Neurosci. 2003 Mar-Aug;25(2-4):139-51. PMID: 12966212 [PubMed - indexed for MEDLINE]
- Cajal-Retzius cells in the mouse: transcription factors, neurotransmitters, and birthdays suggest a pallial origin. Hevner RF, Neogi T, Englund C, Daza RA, Fink A. Brain Res Dev Brain Res. 2003 Mar 14;141(1-2):39-53. PMID: 12644247 [PubMed - indexed for MEDLINE]
For more information on the Hevner Lab, contact:
Ray Anthony M. Daza
Research Scientist II - Hevner Lab Manager
Center for Integrative Brain Research
Seattle Children's Research Institute
Building One, Mailstop C9S-10
1900 Ninth Avenue
Seattle, WA 98101
Phone: (206) 884-8171
Fax: (206) 884-7311