Dana Levasseur Ph.D. [Former faculty]

Eric Van Otterloo Ph.D.

Current
Eric
Van Otterloo
Ph.D.
Assistant Professor
Iowa Institute for Oral Health Research, College of Dentistry; Anatomy and Cell Biology, College of Medicine
Research area(s): 
Craniofacial development genetics; Embryogenesis
Address
N447
DSB
1-632
BSB
Research
Research Focus: 

With birth defects impacting ~3% of all infants born and ~75% of these affecting the head and oral cavity, a comprehensive understanding of the genetic and molecular mechanisms at play is essential. One such mechanism, essential for proper craniofacial development, is finely tuned tissue:tissue communication. However, how these signals are properly generated, augmented, and then interpreted—between tissues—is not well understood. Our lab’s research utilizes a combination of sophisticated animal models, genetics, and modern molecular biology based next generation sequencing approaches to unravel these complex interconnected networks. For example, we are investigating key proteins that are found, and regulate, these various ‘nodes’ of tissue:tissue communication during craniofacial development. In turn, we anticipate the principles discovered will ultimately guide how we understand, predict, and mitigate mechanisms associated with craniofacial birth defects.

Faculty affiliations: 

Ben Darbro M.D., Ph.D.

Current
Ben
Darbro
M.D., Ph.D.
Associate Professor, Director of the Shivanand R. Patil Cytogenetics and Molecular Laboratory
Pediatrics
Research area(s): 
Genetic Determinants of Intellectual Disability
Address
Research
Research Focus: 

My primary research interest is in the genetic determinants of intellectual disability (ID), formerly referred to as mental retardation (MR).  I specifically study the roles of copy number variation and somatic structural variation in the context of a “genomic mutational burden” hypothesis of ID.  This hypothesis is investigated using a combination of conventional cytogenetics methods (chromosome analysis and fluorescence in situ hybridization) and new molecular, high throughput, and high data volume, genomic technologies including single nucleotide polymorphism (SNP) arrays, gene expression microarrays, comparative genomic hybridization (CGH) arrays as well as custom targeted, whole exome, and whole genome massively parallel DNA sequencing.  We perform all our own bioinformatics and are actively engaged in the development of new analysis tools to better meet our needs and those of the scientific community.  Drosophila melanogaster and the well-established GAL4/UAS/RNAi system are used to evaluate candidate ID genes with the use of a validated olfaction learning technique (T-Maze).  Candidate genes are derived from our extensive clinical database of patients with ID that have already undergone diagnostic chromosomal microarray testing.

Albert J Erives PhD

Current
Albert
J
Erives
PhD
Associate Professor
Biology
Research area(s): 
Bioinformatics, Developmental Genetics, Evolutionary Genetics, Gene Expression and Regulation
Address
424A
BB
424
BB
Research
Research Focus: 

The Genetics of Eukaryotic Transcriptional Enhancers

Transcriptional enhancers are DNA sequences that specify inducible, spatiotemporal patterns of gene expression at most gene loci. Several complementary results from genomic studies have shown that the majority of functional sites in a genome correspond to transcriptional enhancer sequences, thus underscoring their importance for understanding basic physiology. However, while transcriptional enhancers represent a major class of regulatory DNAs in eukaryotic genomes, the entire set of sequences that are necessary and sufficient for constructing a complex eukaryotic enhancer are not yet known.

Our laboratory is focused on using molecular biology, genomics, bioinformatics, and transgenic model systems to understand enhancer biology. A major area of focus in our laboratory is the study of how different morphogen-concentration specific responses are encoded at different loci. We are also interested in understanding the sequence-function relationship well enough to understand the complex patterns of molecular evolution occurring at enhancer sequences.

Joshua A. Weiner Ph.D.

Current
Joshua
A.
Weiner
Ph.D.
Professor
Biology
Research area(s): 
Molecular Mechanisms of Neuronal Differentiation and Neural Circuit Formation
Address
348
Biology Building
348
BB
Research
Research Focus: 

Molecular Mechanisms of Neuronal Differentiation and Neural Circuit Formation

 

The mammalian brain is the most complex system in all of biology. The human brain has ~100 billion neurons and perhaps 500 trillion synapses, contact sites between neurons through which information flows. The differentiation of a vast array of distinct neuronal cell types from stem cell progenitors, and their migration to form layers and clusters, is a key developmental step that can be disrupted in human disorders such as microcephaly and lissencephaly. The elaboration of dendrites and axons and their formation of specific neural circuits underlies all mature function, and dysregulation of these processes underlies a wide variety of genetic and syndromic disorders, including forms of autism spectrum disorders, Down and Fragile X Syndromes, and schizophrenia. My laboratory is focused on identifying the fundamental molecular mechanisms that control neuronal differentiation and neural circuit formation during brain development. We take a candidate approach, generating allelic series of transgenic and knockout mice and analyzing their developmental phenotypes with a wide range of genetic, biochemical, pharmacological, molecular biology, and cell biology techniques. We focus on genes and processes that have been implicated in human neurodevelopmental disorders. Multiple projects are available for ambitious graduate students, postdocs, and undergraduate Honors students. Our work has been continuously funded since the lab’s founding in 2004, including grants from the National Institutes of Health, the March of Dimes, the Carver Trust, the Nellie Ball Trust, the Mallinckrodt Foundation, the E. Matilda Ziegler Foundation for the Blind, and the National Multiple Sclerosis Society.

Protocadherins

Three large clusters of cadherin-related genes (Protocadherin-α, -β, and -γ) lie in a tandem array on a single chromosome in mammals. The γ cluster, on which we focus, consists of 22 "variable" exons, each of which encodes the extracellular, transmembrane, and partial cytoplasmic domains of a single protocadherin (Pcdh) isoform. Each variable exon is spliced to a set of three "constant" exons which encode a shared C-terminal domain. Thus, a variety of adhesive specificities can link into a common signaling pathway. Because each neuron expresses ~6 of the isoforms in a semi-stochastic manner, the γ-Pcdhs may provide a “molecular code” that helps specify cell-cell interactions. We have shown that the γ-Pcdhs act as homophilic adhesion molecules, and have identified them as critical mediators of proper dendrite arborization and synaptogenesis in the cerebral cortex. Homophilic trans-interactions between specific γ-Pcdh isoforms on neurons and astrocytes regulates the extent of dendrite outgrowth in vivo. Additionally, cis-interactions between the γ-Pcdhs and the autism-associated protein neuroligin-1 regulate the formation of dendritic spines and excitatory synapses in the cortex. Importantly, epigenetic regulation of γ-Pcdh repertoire is disrupted in neurodevelopmental disorders such as Down syndrome, indicating that the mechanisms we’ve discovered have implications for both normal and disrupted human development. In new work, we’ve used CRISPR/Cas9 genome editing to generate a new series of mice in which γ-Pcdh diversity is reduced. We will use these mice to test hypotheses about the role of molecular specificity in cell-cell interactions in vivo, and to define human disease-relevant behavioral deficits that result from altered γ-Pcdh expression.

Akirins

A key step in the development of the brain is the transition from proliferating neural progenitors to postmitotic neurons that then migrate to their final cellular position and differentiate and elaborate dendrites and axons to form circuits. The molecular mechanisms regulating neuronal differentiation are only partially understood; recent work indicates that chromatin remodeling machinery, which regulates the expression of thousands of genes by altering DNA structure, plays an important role. Akirin2 is a nuclear protein that is known to interact with subunits of the BAF chromatin remodeling complex, but whose function in mammalian cells has been obscure. We found that the Akirin2 gene is expressed in cortical progenitors and in postmitotic cortical neurons, and generated cortex-restricted knockout mice using the Cre/LoxP system to analyze the function of Akirin2. Remarkably, when Akirin2 is absent from cortical progenitors, they completely fail to generate the cerebral cortex, and exhibit an extreme form of microcephaly. Most knockout mice die at birth with little-to-no cortical tissue present; a few survive postnatally, despite lacking a cortex. Analyzing control and knockout transcriptomes using RNA sequencing suggests that Akirin2 is critical for activating genes maintaining progenitor fate, and for repressing the genes associated with neuronal differentiation. Using distinct Cre transgenic lines to limit Akirin2 mutation to astrocytes, we have also found severe defects in the cerebellum indicative of defective neuronal migration and differentiation. These data identify Akirin2 as a novel master regulator of gene expression patterns required for proper neuronal and glial cell fates.

Faculty affiliations: 

Dana Levasseur Ph.D.

Assistant Professor
Internal Medicine

C. Andrew Frank Ph.D.

Current
C. Andrew
Frank
Ph.D.
Associate Professor
Anatomy and Cell Biology
Research area(s): 
Homeostatic Control of Synaptic Function
Address
1-661A
Bowen Science Building
Research
Research Focus: 

Homeostasis is a robust form of regulation that allows a system to maintain a constant output despite external perturbations. In the nervous system, homeostasis plays a critical role in regulating neuronal and synaptic activity. Yet the molecular basis of this form of neural plasticity is generally unknown. We address this problem using the fruit fly, Drosophila melanogaster.  This model allows us to combine electrophysiology with powerful genetic and pharmacological techniques. The overall goal is to define conserved signaling mechanisms that direct synapses to maintain stable properties, like excitation levels.

It is generally believed that molecules controlling the balance of excitation and inhibition within the nervous system influence many neurological diseases. Therefore, understanding synaptic homeostasis is of clinical interest. This area of research could uncover factors with relevance to the cause and progression of disorders such as epilepsy, which reflects a state of poorly controlled neural function.

Faculty affiliations: 

Bryan T Phillips Ph.D.

Current
Bryan
T
Phillips
Ph.D.
Associate Professor
Biology
Research area(s): 
Cell Fate Determination in C. elegans
Address
200
Biology Building East
214
BBE
Research
Research Focus: 

How does an egg become an adult?
The means by which a single undifferentiated oocyte develops into a multicellular organism with numerous, intricately connected cell types is a major focus in developmental biology. Defects in the process of cell fate determination can lead to disease or death. Cell-to-cell communication is a common way that a cell (or a group of cells) is instructed to proceed down one particular developmental path versus another. One way that cells execute these instructions is through asymmetric division of a polarized mother cell, generating two daughter cells that contain different fate determinants and thus proceed down different developmental paths.

C.elegans as a model for developmental genetics
Since all multicellular animals progress through development by overcoming similar developmental obstacles, the molecular mechanisms that overcome these obstacles have often been conserved during evolution. We use the nematode, Caenorhabditis elegans, to address the problem of how cell differentiation works in multicellular animals. C. elegans has many attributes that make it well-suited to study developmental biology, including excellent genetics, transgenics, and a sequenced genome. Especially important for our research, C. elegans also uses conserved cell signaling pathways to polarize mother cells and induce asymmetric divisions throughout its development.

The importance of communication
The Wnt signaling pathway regulates cell fate in many animals, including nematodes and mammals. Wnt signaling stabilizes a transcriptional coactivator called β-catenin, which then binds to TCF/LEF DNA-binding proteins and converts them into activators of Wnt target gene expression. β-catenin regulation is therefore a crucial step in the Wnt signaling pathway. β-catenin mis-regulation is associated with developmental defects and human diseases such as cancer. Wnt signaling also regulates many asymmetric divisions in C. elegans. An essential component of this pathway in C. elegans is SYS-1, which binds TCF transcription factors and upregulates transcription of Wnt target genes much as β-catenin does in other organisms. The crystal structure of SYS-1 confirms that SYS-1 has the structural hallmarks of the β-catenin family of transcriptional coactivators.  SYS-1 shows a remarkable conservation of structure and function when compared to vertebrate β-catenin. We use these similarities (and the differences between the β-catenins) to dissect how β-catenins work. Other areas of interest in the Phillips lab are determining how the Wnt pathway functions in C. elegans, SYS-1/β-catenin regulation, and β-catenin evolution. These studies will help us understand the larger question of why animal cells differentiate the way they do.

Faculty affiliations: 

Sarit Smolikove Ph.D.

Current
Sarit
Smolikove
Ph.D.
Associate Professor
Biology
Research area(s): 
Chromosome dynamics in C. elegans meiosis
Address
Research
Research Focus: 

Our research focuses on the evolutionarily conserved process of meiosis, using C. elegans as a model system. Meiosis enables sexual reproduction by the production of haploid gametes. A successful meiotic division relies on the formation of crossover events between each pair of homologous chromosomes. These crossover events are formed in the context of the synaptonemal complex (SC), a protein complex that bridges paired homologous chromosomes during meiotic prophase I.  Hence, in the absence of a functional SC, meiosis is abrogated. Perturbation of meiosis can lead to chromosome nondisjunction, which is the leading cause for miscarriages and birth defects in humans. These observations, combined with evidence from studies of infertile patients, suggest a connection between SC dysfunction and chromosomal nondisjunction in human reproduction. In our lab we aim to discover and characterize novel genes essential for various aspects of meiosis, including genes essential for chromosome pairing, recombination, and the regulation of SC assembly and disassembly. To accomplish this goal, we are engaged in genetic screens targeted to isolate genes in these processes. This approach has already resulted in the identification of a novel class of mutants affecting SC disassembly. We combine our genetic approaches with high-resolution microscopy to investigate the role of these proteins in meiosis. These studies will result in a better understanding of the various fundamental processes unfolding in C. elegans meiosis and will lead to insights into this basic process in other organisms as well. In-depth investigation of meiosis is of central importance for progress in developing methods to prevent and treat infertility and birth defects stemming from meiotic chromosome nondisjunction in humans.

Faculty affiliations: 

Tina Tootle Ph.D.

Current
Tina
Tootle
Ph.D.
Associate Professor
Anatomy and Cell Biology
Research area(s): 
Understanding the mechanisms of prostaglandin signaling
Address
Research
Research Focus: 

Prostaglandins are transiently acting hormones that are synthesized at their sites of action by cyclooxygenase (COX) enzymes, the targets of Aspirin and Advil, to mediate a variety of biological activities, including inflammation, sleep, reproduction, and cancer development. How do prostaglandins regulate these diverse, cellular events? To address this question we have developed Drosophila oogenesis as a new a new and powerful model for studying prostaglandin signaling. Using both pharmacology and genetics, we discovered that prostaglandins mediate Drosophila follicle development, identified the Drosophila COX1 enzyme, Pxt, and revealed that genetic perturbation of prostaglandin signaling can be used to exam the function of prostaglandins. This research on prostaglandin signaling implicates it in modulating actin/membrane dynamics, cell migration, stem cell activity, and the timing of gene expression during Drosophila follicle development. The lab is currently pursuing how prostaglandin signaling regulates actin dynamics and invasive cell migrations during Drosophila follicle development. By using a multifaceted experimental approach that combines Drosophila genetics, cell biology, live imaging, and biochemistry to we can begin to work out the mechanisms by which prostaglandins regulate these processes, and provide general insight into how prostaglandins regulate the cytoskeleton and migration at a cellular level. Such mechanisms of prostaglandin action are likely to be reutilized throughout development, including mediating the changes that occur during cancer progression and metastasis.

Chun-Fang Wu Ph.D.

Current
Chun-Fang
Wu
Ph.D.
Professor
Biology
Research area(s): 
Neurogenetics of Drosophila
Address
237
BB
231
BB
Research
Research Focus: 

Major research interests in this laboratory concern the genetic control of function and development of the nervous system. Currently we focus on mutants of the fruit fly Drosophila with altered nerve excitability and deficiencies in learning behavior.  The effects of single-gene mutations and their interactions in double mutants provide clues for the functional organizations of the ionic channels and second messenger pathways that govern neuronal activities and synaptic plasticity.
Mutant alleles and conditional expression of transients are analyzed to elucidate experience-dependent plasticity in the development of the functional organization in the nervous system. The effects of altered nerve activity and physiological actions on the path finding, arborization, and generation of neural connectivities are determined in neuronal cultures as well as in genetic mosaics.

Faculty affiliations: 

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