Scholars@Duke
Debra Lynn Silver

Debra Lynn Silver

Professor of Molecular Genetics and Microbiology
Molecular Genetics and Microbiology

Selected Publications

The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton.

Journal Article Cell Rep · September 24, 2024 The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. We discover that EIF4A3 directly controls microtubules, independent of RNA, which is critical for neural wiring. While neuronal surviva ... Full text Link to item Cite

A human-specific enhancer fine-tunes radial glia potency and corticogenesis.

Journal Article bioRxiv · April 11, 2024 Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications 1-3 . Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutio ... Full text Link to item Cite

A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X.

Journal Article Mol Syst Biol · March 2024 The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulate ... Full text Link to item Cite

What approaches are needed to understand human development and disease?

Journal Article Dev Cell · December 18, 2023 Researchers are leveraging what we have learned from model organisms to understand if the same principles arise in human physiology, development, and disease. In this collection of Voices, we asked researchers from different fields to discuss what tools an ... Full text Link to item Cite

The exon junction complex component EIF4A3 is essential for mouse and human cortical progenitor mitosis and neurogenesis.

Journal Article Development (Cambridge, England) · May 2023 Mutations in components of the exon junction complex (EJC) are associated with neurodevelopment and disease. In particular, reduced levels of the RNA helicase EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS) and copy number variations are linked to inte ... Full text Cite

Subcellular mRNA localization and local translation of Arhgap11a in radial glial progenitors regulates cortical development.

Journal Article Neuron · March 15, 2023 mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in polarized, elongated cells. These features are especially prominent in radial glial cells (RGCs), which are neural and glial precursor ... Full text Link to item Cite

Non-muscle myosins control radial glial basal endfeet to mediate interneuron organization.

Journal Article PLoS Biol · February 2023 Radial glial cells (RGCs) are essential for the generation and organization of neurons in the cerebral cortex. RGCs have an elongated bipolar morphology with basal and apical endfeet that reside in distinct niches. Yet, how this subcellular compartmentaliz ... Full text Link to item Cite

Posttranscriptional Control of Brain Development

Chapter · January 1, 2023 The neocortex is among the newest evolutionary additions to the human brain, consistent with its function in higher-level processes such as cognition. This structure develops through neural progenitor proliferation, neural differentiation, neuronal migrati ... Full text Cite

Adaptive sequence divergence forged new neurodevelopmental enhancers in humans.

Journal Article Cell · November 23, 2022 Searches for the genetic underpinnings of uniquely human traits have focused on human-specific divergence in conserved genomic regions, which reflects adaptive modifications of existing functional elements. However, the study of conserved regions excludes ... Full text Open Access Link to item Cite

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model.

Journal Article Elife · June 28, 2022 Mutations in the RNA helicase, DDX3X, are a leading cause of Intellectual Disability and present as DDX3X syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet, the cellular and molecular mechanisms by which DDX3X c ... Full text Link to item Cite

Post-transcriptional Gene Regulation During Cortical Development

Chapter · January 1, 2022 Higher-order cognitive function in mammals is derived from the activity of the cerebral cortex. This brain structure is among the most complex tissues in the body, and its development requires multiple layers of regulation. The network of transcription fac ... Full text Cite

Human brain evolution: Emerging roles for regulatory DNA and RNA.

Journal Article Current opinion in neurobiology · December 2021 Humans diverge from other primates in numerous ways, including their neuroanatomy and cognitive capacities. Human-specific features are particularly prominent in the cerebral cortex, which has undergone an expansion in size and acquired unique cellular com ... Full text Cite

Uncovering the HARbingers of human brain evolution.

Journal Article Neuron · October 20, 2021 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 acceler ... Full text Link to item Cite

Expanding gliogenesis.

Journal Article Science · June 11, 2021 Full text Link to item Cite

Founder cells shape brain evolution.

Journal Article Cell · April 15, 2021 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 ... Full text Link to item Cite

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

Journal Article Curr Opin Neurobiol · February 2021 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 dev ... Full text Link to item Cite

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

Journal Article Traffic · December 2020 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 bip ... Full text Link to item Cite

Evolution: Does More Time Buy More Neurons?

Journal Article Curr Biol · November 2, 2020 Brain expansion and increased neuronal number are hallmarks of cortical evolution, particularly in humans. A new study establishes a link between the length of gestation, neurogenesis, the maternal environment, and key features associated with more complex ... Full text Link to item Cite

Subcellular mRNA localization and local translation of Arhgap11a in radial glial cells regulates cortical development

Journal Article bioRxiv · July 31, 2020 mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in highly polarized and elongated cells. These features are especially prominent in radial glial cells (RGCs), which serve as neural and ... Full text Open Access Cite

Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development.

Journal Article Neuron · May 6, 2020 De novo germline mutations in the RNA helicase DDX3X account for 1%-3% of unexplained intellectual disability (ID) cases in females and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which ... Full text Link to item Cite

Intravital imaging of mouse embryos.

Journal Article Science · April 10, 2020 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 manip ... Full text Open Access Link to item Cite

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

Journal Article Development · January 13, 2020 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-depend ... Full text Link to item Cite

Posttranscriptional and translational control of neurogenesis

Chapter · January 1, 2020 The sequential events of neurogenesis are orchestrated by diverse layers of molecular regulation, including posttranscriptional control. Notably, while a great deal is known about transcriptional and signaling hierarchies in neurogenesis, in comparison, we ... Full text Cite

Damage Control in the Developing Brain: Tradeoffs and Consequences.

Journal Article Trends Neurosci · October 2019 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 que ... Full text Link to item Cite

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo.

Journal Article Dev Neurosci · 2019 BACKGROUND/AIMS: Prenatal microcephaly is posited to arise from aberrant mitosis of neural progenitors, which disrupts both neuronal production and survival. Although microcephaly has both a genetic and environmental etiology, the mechanisms by which dysre ... Full text Link to item Cite

Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1.

Journal Article J Cell Biol · October 1, 2018 Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy and neuropathic pain; thus the TSP-α2δ-1 interaction is imp ... Full text Link to item Cite

Progenitor Hyperpolarization Regulates the Sequential Generation of Neuronal Subtypes in the Developing Neocortex.

Journal Article Cell · August 23, 2018 During corticogenesis, ventricular zone progenitors sequentially generate distinct subtypes of neurons, accounting for the diversity of neocortical cells and the circuits they form. While activity-dependent processes are critical for the differentiation an ... Full text Link to item Cite

Enhancing our brains: Genomic mechanisms underlying cortical evolution.

Journal Article Semin Cell Dev Biol · April 2018 Our most distinguishing higher cognitive functions are controlled by the cerebral cortex. Comparative studies detail abundant anatomical and cellular features unique to the human developing and adult neocortex. Emerging genomic studies have further defined ... Full text Link to item Cite

A Fluorescent Cell-Based System for Imaging Zika Virus Infection in Real-Time.

Journal Article Viruses · February 24, 2018 Zika virus (ZIKV) is a re-emerging flavivirus that is transmitted to humans through the bite of an infected mosquito or through sexual contact with an infected partner. ZIKV infection during pregnancy has been associated with numerous fetal abnormalities, ... Full text Link to item Cite

RNA on the brain: emerging layers of post-transcriptional regulation in cerebral cortex development.

Journal Article Wiley Interdiscip Rev Dev Biol · January 2018 Embryonic development is a critical period during which neurons of the brain are generated and organized. In the developing cerebral cortex, this requires complex processes of neural progenitor proliferation, neuronal differentiation, and migration. Each s ... Full text Link to item Cite

EIF4A3 deficient human iPSCs and mouse models demonstrate neural crest defects that underlie Richieri-Costa-Pereira syndrome.

Journal Article Hum Mol Genet · June 15, 2017 Biallelic loss-of-function mutations in the RNA-binding protein EIF4A3 cause Richieri-Costa-Pereira syndrome (RCPS), an autosomal recessive condition mainly characterized by craniofacial and limb malformations. However, the pathogenic cellular mechanisms r ... Full text Link to item Cite

Moving messages in the developing brain-emerging roles for mRNA transport and local translation in neural stem cells.

Journal Article FEBS Lett · June 2017 The mammalian cerebral cortex is a complex brain structure integral to our higher cognition. During embryonic cortical development, radial glial progenitors (RGCs) produce neurons and serve as physical structures for migrating neurons. Recent discoveries h ... Full text Link to item Cite

Mouse models of Casc3 reveal developmental functions distinct from other components of the exon junction complex.

Journal Article RNA · January 2017 The exon junction complex (EJC) is a multiprotein complex integral to mRNA metabolism. Biochemistry and genetic studies have concluded that the EJC is composed of four core proteins, MAGOH, EIF4A3, RBM8A, and CASC3. Yet recent studies in Drosophila indicat ... Full text Link to item Cite

Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain.

Journal Article Curr Biol · December 19, 2016 In the developing brain, neurons are produced from neural stem cells termed radial glia [1, 2]. Radial glial progenitors span the neuroepithelium, extending long basal processes to form endfeet hundreds of micrometers away from the soma. Basal structures i ... Full text Link to item Cite

The exon junction complex in neural development and neurodevelopmental disease.

Journal Article Int J Dev Neurosci · December 2016 Post-transcriptional mRNA metabolism has emerged as a critical regulatory nexus in proper development and function of the nervous system. In particular, recent studies highlight roles for the exon junction complex (EJC) in neurodevelopment. The EJC is an R ... Full text Link to item Cite

Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly.

Journal Article PLoS Genet · September 2016 The exon junction complex (EJC) is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberra ... Full text Open Access Link to item Cite

Genomic divergence and brain evolution: How regulatory DNA influences development of the cerebral cortex.

Journal Article Bioessays · February 2016 The cerebral cortex controls our most distinguishing higher cognitive functions. Human-specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review di ... Full text Link to item Cite

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Journal Article Cell · January 14, 2016 Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of ... Full text Link to item Cite

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

Journal Article Neuron · January 6, 2016 Featured Publication 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. ... Full text Link to item Cite

Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly.

Journal Article J Neurosci · May 6, 2015 Featured Publication The cerebral cortex is built during embryonic neurogenesis, a period when excitatory neurons are generated from progenitors. Defects in neurogenesis can cause acute neurodevelopmental disorders, such as microcephaly (reduced brain size). Altered dosage of ... Full text Link to item Cite

Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex.

Journal Article Curr Biol · March 16, 2015 Featured Publication The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [1-5]. Although these evolutionary changes most likely contributed to the origin of distinctive ... Full text Open Access Link to item Cite

Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain.

Journal Article Wiley Interdiscip Rev RNA · 2015 The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. During corticogenesis, neural stem cells generate distinct populations of progenitors and exc ... Full text Link to item Cite

Astrocytes refine cortical connectivity at dendritic spines.

Journal Article Elife · December 17, 2014 During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. ... Full text Open Access Link to item Cite

Elucidating the role of the RNA binding exon junction complex in mitosis

Conference MOLECULAR BIOLOGY OF THE CELL · December 1, 2014 Link to item Cite

Generation of a Magoh conditional allele in mice.

Journal Article Genesis · August 2014 Magoh encodes a core component of the exon junction complex (EJC), which binds mRNA and regulates mRNA metabolism. Magoh is highly expressed in proliferative tissues during development. EJC components have been implicated in several developmental disorders ... Full text Link to item Cite

Live imaging of mitosis in the developing mouse embryonic cortex.

Journal Article J Vis Exp · June 4, 2014 Although of short duration, mitosis is a complex and dynamic multi-step process fundamental for development of organs including the brain. In the developing cerebral cortex, abnormal mitosis of neural progenitors can cause defects in brain size and functio ... Full text Link to item Cite

Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy.

Journal Article Neuron · October 16, 2013 We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible f ... Full text Link to item Cite

Genetic interaction screens identify a role for hedgehog signaling in Drosophila border cell migration.

Journal Article Dev Dyn · May 2013 BACKGROUND: Cell motility is essential for embryonic development and physiological processes such as the immune response, but also contributes to pathological conditions such as tumor progression and inflammation. However, our understanding of the mechanis ... Full text Link to item Cite

The EJC component Magoh regulates proliferation and expansion of neural crest-derived melanocytes.

Journal Article Dev Biol · March 15, 2013 Melanoblasts are a population of neural crest-derived cells that generate the pigment-producing cells of our body. Defective melanoblast development and function underlies many disorders including Waardenburg syndrome and melanoma. Understanding the geneti ... Full text Link to item Cite

The exon junction complex component Magoh controls brain size by regulating neural stem cell division.

Journal Article Nat Neurosci · May 2010 Brain structure and size require precise division of neural stem cells (NSCs), which self-renew and generate intermediate neural progenitors (INPs) and neurons. The factors that regulate NSCs remain poorly understood, and mechanistic explanations of how ab ... Full text Open Access Link to item Cite

ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression.

Journal Article Dev Cell · November 2009 We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5(-/-);bt/bt mice had reduced apoptosis and decreased cleavage of th ... Full text Link to item Cite

A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.

Journal Article Hum Mol Genet · July 15, 2008 Haploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10(LacZ/+)). As genetic background affects WS severity in both humans and m ... Full text Link to item Cite

The secreted metalloprotease ADAMTS20 is required for melanoblast survival.

Journal Article PLoS Genet · February 29, 2008 ADAMTS20 (Adisintegrin-like and metalloprotease domain with thrombospondin type-1 motifs) is a member of a family of secreted metalloproteases that can process a variety of extracellular matrix (ECM) components and secreted molecules. Adamts20 mutations in ... Full text Open Access Link to item Cite

The origin and development of neural crest-derived melanocytes

Journal Article · December 1, 2006 Melanocytes are specified from pluripotent neural crest cells that delaminate from the developing neural tube and overlying ectoderm early in development. As a subset of these neural crest cells migrate along the dorsal-lateral path, they begin to differen ... Full text Cite

The genetic regulation of pigment cell development.

Journal Article Adv Exp Med Biol · 2006 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 th ... Full text Link to item Cite

Requirement for JAK/STAT signaling throughout border cell migration in Drosophila.

Journal Article Development · August 2005 The evolutionarily conserved JAK/STAT signaling pathway is essential for the proliferation, survival and differentiation of many cells including cancer cells. Recent studies have implicated this transcriptional pathway in the process of cell migration in h ... Full text Link to item Cite

Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility.

Journal Article Cancer Res · May 15, 2004 Constitutive activation of the Janus-activated kinase/signal transducer and activator of transcription (STAT) pathway promotes the proliferation and survival of cancer cells in culture and is associated with various cancers, including those of the ovary. W ... Full text Link to item Cite

A new trick for Cyclin-Cdk: activation of STAT.

Journal Article Dev Cell · February 2003 New work in Drosophila demonstrates that cdk4 loss causes phenotypes similar to the loss of JAK/STAT pathway components. Cdk4 overexpression can bypass requirements for JAK but not STAT. These results demonstrate a new function for Cdk4 and a new mode of S ... Full text Link to item Cite

Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila.

Journal Article Cell · December 28, 2001 The JAK/STAT signaling pathway, renowned for its effects on cell proliferation and survival, is constitutively active in various human cancers, including ovarian. We have found that JAK and STAT are required to convert the border cells in the Drosophila ov ... Full text Link to item Cite

Requirement for the vasa RNA helicase in gurken mRNA localization.

Journal Article Dev Biol · July 1, 1998 Localization of specific mRNAs to distinct sites within the Drosophila oocyte is an early and key step in establishing the anterior-posterior and dorsal-ventral axes. We describe a new function for the RNA helicase encoded by the "posterior" group gene vas ... Full text Link to item Cite

Tyrosine phosphorylation of the beta3 cytoplasmic domain mediates integrin-cytoskeletal interactions.

Journal Article J Biol Chem · May 29, 1998 Tyrosine phosphorylation of the beta3 subunit of the major platelet integrin alphaIIb beta3 has been shown to occur during thrombin-induced platelet aggregation (1). We now show that a wide variety of platelet stimuli induced beta3 tyrosine phosphorylation ... Full text Link to item Cite

Effect of Mts1 on the structure and activity of nonmuscle myosin II.

Journal Article Biochemistry · December 23, 1997 The mts1 gene codes for a 9 kDa protein belonging to the S100 subfamily of Ca2+-binding proteins and is known to play a role in metastasis. Its role in metastasis may be through cellular locomotion, as transfection of mts1 into mouse mammary adenocarcinoma ... Full text Link to item Cite

Sites of interaction between kinase-related protein and smooth muscle myosin.

Journal Article J Biol Chem · October 3, 1997 Kinase-related protein, also known as KRP or telokin, is an independently expressed protein product derived from a gene within the gene for myosin light chain kinase (MLCK). KRP binds to unphosphorylated smooth muscle myosin filaments and stabilizes them a ... Full text Link to item Cite