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 Regeneration Next Initiative

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
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:

Intravital imaging of mouse embryos.

Embryonic development is a complex process that is unamenable to direct observation. In this study, we implanted a window to the mouse uterus to visualize the developing embryo from embryonic day 9.5 to birth. This removable intravital window allowed manipulation and high-resolution imaging. In live mouse embryos, we observed transient neurotransmission and early vascularization of neural crest cell (NCC)-derived perivascular cells in the brain, autophagy in the retina, viral gene delivery, and chemical diffusion through the placenta. We combined the imaging window with in utero electroporation to label and track cell division and movement within embryos and observed that clusters of mouse NCC-derived cells expanded in interspecies chimeras, whereas adjacent human donor NCC-derived cells shrank. This technique can be combined with various tissue manipulation and microscopy methods to study the processes of development at unprecedented spatiotemporal resolution.
Authors
Huang, Q; Cohen, MA; Alsina, FC; Devlin, G; Garrett, A; McKey, J; Havlik, P; Rakhilin, N; Wang, E; Xiang, K; Mathews, P; Wang, L; Bock, C; Ruthig, V; Wang, Y; Negrete, M; Wong, CW; Murthy, PKL; Zhang, S; Daniel, AR; Kirsch, DG; Kang, Y; Capel, B; Asokan, A; Silver, DL; Jaenisch, R; Shen, X
MLA Citation
Huang, Qiang, et al. “Intravital imaging of mouse embryos.Science, vol. 368, no. 6487, Apr. 2020, pp. 181–86. Pubmed, doi:10.1126/science.aba0210.
URI
https://scholars.duke.edu/individual/pub1436476
PMID
32273467
Source
pubmed
Published In
Science
Volume
368
Published Date
Start Page
181
End Page
186
DOI
10.1126/science.aba0210

Dosage-dependent requirements of Magoh for cortical interneuron generation and survival.

Embryonic interneuron development underlies cortical function and its disruption contributes to neurological disease. Yet the mechanisms by which viable interneurons are produced from progenitors remain poorly understood. Here, we demonstrate dosage-dependent requirements of the exon junction complex component Magoh for interneuron genesis in mouse. Conditional Magoh ablation from interneuron progenitors, but not post-mitotic neurons, depletes cortical interneuron number through adulthood, with increased severity in homozygotes. Using live imaging, we discover that Magoh deficiency delays progenitor mitotic progression in a dosage-sensitive fashion, with 40% of homozygous progenitors failing to divide. This shows that Magoh is required in progenitors for both generation and survival of newborn progeny. Transcriptome analysis implicates p53 signaling; moreover, p53 ablation in Magoh haploinsufficient progenitors rescues apoptosis, completely recovering interneuron number. In striking contrast, in Magoh homozygotes, p53 loss fails to rescue interneuron number and mitotic delay, further implicating mitotic defects in interneuron loss. Our results demonstrate that interneuron development is intimately dependent upon progenitor mitosis duration and uncover a crucial post-transcriptional regulator of interneuron fate relevant for neurodevelopmental pathologies.This article has an associated 'The people behind the papers' interview.
Authors
Sheehan, CJ; McMahon, JJ; Serdar, LD; Silver, DL
MLA Citation
Sheehan, Charles J., et al. “Dosage-dependent requirements of Magoh for cortical interneuron generation and survival.Development, vol. 147, no. 1, Jan. 2020. Pubmed, doi:10.1242/dev.182295.
URI
https://scholars.duke.edu/individual/pub1424245
PMID
31857347
Source
pubmed
Published In
Development
Volume
147
Published Date
DOI
10.1242/dev.182295

Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain.

Embryonic neocortical development depends on balanced production of progenitors and neurons. Genetic mutations disrupting progenitor mitosis frequently impair neurogenesis; however, the link between altered mitosis and cell fate remains poorly understood. Here we demonstrate that prolonged mitosis of radial glial progenitors directly alters neuronal fate specification and progeny viability. Live imaging of progenitors from a neurogenesis mutant, Magoh(+/-), reveals that mitotic delay significantly correlates with preferential production of neurons instead of progenitors, as well as apoptotic progeny. Independently, two pharmacological approaches reveal a causal relationship between mitotic delay and progeny fate. As mitotic duration increases, progenitors produce substantially more apoptotic progeny or neurons. We show that apoptosis, but not differentiation, is p53 dependent, demonstrating that these are distinct outcomes of mitotic delay. Together our findings reveal that prolonged mitosis is sufficient to alter fates of radial glia progeny and define a new paradigm to understand how mitosis perturbations underlie brain size disorders such as microcephaly.
Authors
Pilaz, L-J; McMahon, JJ; Miller, EE; Lennox, AL; Suzuki, A; Salmon, E; Silver, DL
MLA Citation
Pilaz, Louis-Jan, et al. “Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain.Neuron, vol. 89, no. 1, Jan. 2016, pp. 83–99. Pubmed, doi:10.1016/j.neuron.2015.12.007.
URI
https://scholars.duke.edu/individual/pub1071301
PMID
26748089
Source
pubmed
Published In
Neuron
Volume
89
Published Date
Start Page
83
End Page
99
DOI
10.1016/j.neuron.2015.12.007

The genetic regulation of pigment cell development.

Pigment cells in developing vertebrates are derived from a transient and pluripotent population of cells called neural crest. The neural crest delaminates from the developing neural tube and overlying ectoderm early in development. The pigment cells are the only derivative to migrate along the dorso-lateral pathway. As they migrate, the precursor pigment cell population differentiates and expands through proliferation and pro-survival processes, ultimately contributing to the coloration of organisms. The types of pigment cells that develop, timing of these processes, and final destination can vary between organisms. Studies from mice, chick, Xenopus, zebrafish, and medaka have led to the identification of many genes that regulate pigment cell development. These include several classes of proteins: transcription factors, transmembrane receptors, and extracellular ligands. This chapter discusses an overview of pigment cell development and the genes that regulate this important process.
Authors
Silver, DL; Hou, L; Pavan, WJ
MLA Citation
Silver, Debra L., et al. “The genetic regulation of pigment cell development.Adv Exp Med Biol, vol. 589, 2006, pp. 155–69. Pubmed, doi:10.1007/978-0-387-46954-6_9.
URI
https://scholars.duke.edu/individual/pub798382
PMID
17076280
Source
pubmed
Published In
Advances in Experimental Medicine and Biology
Volume
589
Published Date
Start Page
155
End Page
169
DOI
10.1007/978-0-387-46954-6_9

Damage Control in the Developing Brain: Tradeoffs and Consequences.

Genomic surveillance is crucial for shaping brain development. However, are these mechanisms always beneficial, and can they be manipulated to ameliorate neurodevelopmental disease? A recent paper by Shi et al. (Nat. Commun., 2019) sheds light on these questions and examines the consequences of both inducing genomic instability and suppressing safeguard mechanisms for the development of the cerebral cortex.
Authors
Alsina, FC; Silver, DL
MLA Citation
Alsina, Fernando C., and Debra L. Silver. “Damage Control in the Developing Brain: Tradeoffs and Consequences.Trends Neurosci, vol. 42, no. 10, Oct. 2019, pp. 661–63. Pubmed, doi:10.1016/j.tins.2019.08.004.
URI
https://scholars.duke.edu/individual/pub1406462
PMID
31447171
Source
pubmed
Published In
Trends Neurosci
Volume
42
Published Date
Start Page
661
End Page
663
DOI
10.1016/j.tins.2019.08.004

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