Debra Silver

Overview:

How is the brain assembled and sculpted during embryonic development?  Addressing this question has enormous implications for understanding neurodevelopmental disorders affecting brain size and function. In evolutionary terms, our newest brain structure is the cerebral cortex, which drives higher cognitive capacities. The overall mission of my research lab is to elucidate genetic and cellular mechanisms controlling cortical development and contributing to neurodevelopmental pathologies and brain evolution. We study neural progenitors, essential cells which generate neurons and are the root of brain development. We are guided by the premise that the same mechanisms at play during normal development were co-opted during evolution and when dysregulated, can cause neurodevelopmental disease.

My research program employs a multifaceted strategy to bridge developmental neurobiology, RNA biology, and evolution. 1) We investigate how cell fates are specified, by studying how progenitor divisions influence development and disease.  2) We study diverse layers of post-transcriptional regulation in neural progenitors. We investigate RNA binding proteins implicated in development and neurological disease. Using live imaging, we also investigate how sub-cellular control of mRNA localization and translation influences neural progenitors. 3) A parallel research focus is to understand how human-specific genetic changes influence species-specific brain development. Our goal is to integrate our efforts across these three major lines of research to understand the intricacies controlling brain development.

Positions:

Associate Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Associate Professor in Cell Biology

Cell Biology
School of Medicine

Associate Professor of Neurobiology

Neurobiology
School of Medicine

Investigator in the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

B.S. 1993

Tufts University

Ph.D. 2003

Johns Hopkins University

Postdoctoral Fellowship, National Human Genome Research Institute

National Institutes of Health

Grants:

Amelioration of neural stem cell defects underlying Zika virus induced microcephaly

Administered By
Molecular Genetics and Microbiology
Awarded By
Hartwell Foundation
Role
Principal Investigator
Start Date
End Date

Zika virus infection of neural stem cells to model pathogen-induced microcephaly

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Distal mRNA localization and translation in neural stem cells of the developing brain

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Post-transcriptional RNA regulation in mammalian neural stem cells

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Mechanisms of neural progenitor division in the developing brain

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Uncovering the HARbingers of human brain evolution.

During evolution, humans acquired extensive genomic changes that collectively define unique features of our species, yet functions for these sequence variants are largely unknown. In this issue of Neuron, Girskis et al. comprehensively screen human accelerated regions (HARs) for enhancer activity in human-specific cortical development, creating a valuable online resource.
Authors
Mosti, F; Silver, DL
MLA Citation
Mosti, Federica, and Debra L. Silver. “Uncovering the HARbingers of human brain evolution.Neuron, vol. 109, no. 20, Oct. 2021, pp. 3231–33. Pubmed, doi:10.1016/j.neuron.2021.09.022.
URI
https://scholars.duke.edu/individual/pub1499740
PMID
34672980
Source
pubmed
Published In
Neuron
Volume
109
Published Date
Start Page
3231
End Page
3233
DOI
10.1016/j.neuron.2021.09.022

Expanding gliogenesis.

Authors
Baldwin, KT; Silver, DL
MLA Citation
Baldwin, Katherine T., and Debra L. Silver. “Expanding gliogenesis.Science, vol. 372, no. 6547, June 2021, pp. 1151–52. Pubmed, doi:10.1126/science.abj1139.
URI
https://scholars.duke.edu/individual/pub1485774
PMID
34112682
Source
pubmed
Published In
Science
Volume
372
Published Date
Start Page
1151
End Page
1152
DOI
10.1126/science.abj1139

Founder cells shape brain evolution.

Humans have an extraordinarily expanded and complex cerebral cortex, relative to non-human primates. Yet the mechanisms underlying cortical differences across evolution are unclear. A new study by Benito-Kwiecinski et al. employs cerebral organoids derived across great apes to implicate neuroepithelial progenitor shape transitions in human cortical expansion.
Authors
Liu, J; Silver, DL
MLA Citation
Liu, Jing, and Debra L. Silver. “Founder cells shape brain evolution.Cell, vol. 184, no. 8, Apr. 2021, pp. 1965–67. Pubmed, doi:10.1016/j.cell.2021.03.045.
URI
https://scholars.duke.edu/individual/pub1480406
PMID
33861961
Source
pubmed
Published In
Cell
Volume
184
Published Date
Start Page
1965
End Page
1967
DOI
10.1016/j.cell.2021.03.045

Decoding mixed messages in the developing cortex: translational regulation of neural progenitor fate.

Regulation of stem cell fate decisions is elemental to faithful development, homeostasis, and organismal fitness. Emerging data demonstrate pluripotent stem cells exhibit a vast transcriptional landscape, which is refined as cells differentiate. In the developing neocortex, transcriptional priming of neural progenitors, coupled with post-transcriptional control, is critical for defining cell fates of projection neurons. In particular, radial glial progenitors exhibit dynamic post-transcriptional regulation, including subcellular mRNA localization, RNA decay, and translation. These processes involve both cis-regulatory and trans-regulatory factors, many of which are implicated in neurodevelopmental disease. This review highlights emerging post-transcriptional mechanisms which govern cortical development, with a particular focus on translational control of neuronal fates, including those relevant for disease.
Authors
Hoye, ML; Silver, DL
MLA Citation
Hoye, Mariah L., and Debra L. Silver. “Decoding mixed messages in the developing cortex: translational regulation of neural progenitor fate.Curr Opin Neurobiol, vol. 66, Feb. 2021, pp. 93–102. Pubmed, doi:10.1016/j.conb.2020.10.001.
URI
https://scholars.duke.edu/individual/pub1463422
PMID
33130411
Source
pubmed
Published In
Curr Opin Neurobiol
Volume
66
Published Date
Start Page
93
End Page
102
DOI
10.1016/j.conb.2020.10.001

Local gene regulation in radial glia: Lessons from across the nervous system.

Radial glial cells (RGCs) are progenitors of the cerebral cortex which produce both neurons and glia during development. Given their central role in development, RGC dysfunction can result in diverse neurodevelopmental disorders. RGCs have an elongated bipolar morphology that spans the entire radial width of the cortex and ends in basal endfeet connected to the pia. The basal process and endfeet are important for proper guidance of migrating neurons and are implicated in signaling. However, endfeet must function at a great distance from the cell body. This spatial separation suggests a role for local gene regulation in endfeet. Endfeet contain a local transcriptome enriched for cytoskeletal and signaling factors. These localized mRNAs are actively transported from the cell body and can be locally translated in endfeet. Yet, studies of local gene regulation in RGC endfeet are still in their infancy. Here, we draw comparisons of RGCs with foundational work in anatomically and phylogenetically related cell types, neurons and astrocytes. Our review highlights a striking overlap in the types of RNAs localized, as well as principles of local translation between these three cell types. Thus, studies in neurons, astrocytes and RGCs can mutually inform an understanding of RNA localization across the nervous system.
Authors
D'Arcy, BR; Silver, DL
MLA Citation
D’Arcy, Brooke R., and Debra L. Silver. “Local gene regulation in radial glia: Lessons from across the nervous system.Traffic, vol. 21, no. 12, Dec. 2020, pp. 737–48. Pubmed, doi:10.1111/tra.12769.
URI
https://scholars.duke.edu/individual/pub1462163
PMID
33058331
Source
pubmed
Published In
Traffic
Volume
21
Published Date
Start Page
737
End Page
748
DOI
10.1111/tra.12769

Research Areas:

Adolescent
Animals
Aspartate-Ammonia Ligase
Atrophy
Body Patterning
Brain
Brain Chemistry
Cell Count
Cell Line
Cell Proliferation
Child
Electroporation
Embryo, Mammalian
Exons
Female
G2 Phase Cell Cycle Checkpoints
Gene Deletion
Gene Expression Regulation, Developmental
Gene Targeting
Genetic Predisposition to Disease
Haploinsufficiency
Homozygote
Humans
Hypopigmentation
Image Processing, Computer-Assisted
In Situ Hybridization
Infant
Infant, Newborn
Intellectual Disability
Male
Melanocytes
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microcephaly
Mitosis
Mutation, Missense
Neural Crest
Neural Stem Cells
Nuclear Proteins
Organ Specificity
Pedigree
SOXE Transcription Factors
Syndrome