Research Description

Topic 1. Mechanisms underlying dopamine neurogenesis
The floor plate, the ventral organizing center in the embryonic neural tube, patterns the neural tube by secreting the potent morphogen Shh. Using genetic fate mapping, we have recently shown that the midbrain floor plate, unlike the hindbrain and spinal cord floor plate, is neurogenic and is the source of midbrain dopamine neurons (Joksimovic, et al, 2009 Nature Neuroscience, Joksimovic et al. 2009 PNAS). We are interested in understanding pathways that are involved in floor plate neurogenesis and production of dopamine neurons. We have shown that Wnt signaling is critical for the establishment of the dopamine progenitor pool and that miRNAs may modulate the dosage and timing of the Wnt pathway (Anderegg et al, PloS Genetics 2013).

Topic 2. Deconstructing Dopaminergic Diversity
The neurotransmitter dopamine, produced mainly by midbrain dopaminergic neurons, influences a spectrum of behaviors including motor, learning, reward, motivation, and cognition.  In accordance with its diverse functions, dopaminergic dysfunction is implicated in a range of disorders affecting millions of people, including Parkinson’s disease (PD), schizophrenia, addiction, and depression. How a small group of neurons underpins a gamut of key behaviors and diseases remains enigmatic. We postulated that there must exist several molecularly distinct dopaminergic neuron populations that, in part, can account for the plethora of dopaminergic functions and disorders. We are currently working to test this hypothesis and define dopamine neuron subtypes.

Topic 3. MicroRNAs in Schwann cell (SC) differentiation
MicroRNAs, by modulating gene expression, have been implicated as regulators of various cellular and physiological processes including differentiation, proliferation, and cancer. We have studied the role of microRNAs in Schwann cell (SC) differentiation by conditional removal of the microRNA processing enzyme, Dicer1 (Yun et al, 2010, J Neurosci) . We reveal that mice lacking Dicer1 in SC (Dicer1 cKO) display a severe neurological phenotype resembling congenital hypomyelination. SC lacking Dicer1 are stalled in differentiation at the promyelinating state and fail to myelinate axons. We are beginning to determine the molecular basis of this phenotype. Understanding this will be important not only for congenital hypomyelination, but also for peripheral nerve regeneration and SC cancers.

For more information, please see Dr. Awatramani's faculty profile.

Publications

View Dr. Awatramani's complete list of publications in PubMed.

Contact Us

Rajeshwar Awatramani, PhD at 312-503-0690

Research Assistant Professor

Giuliana Caronia-Brown

Postdoctoral Fellow

Jean-Francois Poulin

Research Associate

Jian Zou

Graduate Students

Hsin-Pin Lin, MSTP
Navid Nouri, NUIN

Undergraduate Student

Idil Oksuz

Alumni

Milan Joksimovic, Assistant Professor, Medical College of Wisconsin
Angela Anderegg, postdoctoral fellow
Natalya Cherepanova, MSTP student, U. Iowa
Meera Patel, graduate student, U. of Chicago
Beth Yun

Research Description

The Feng lab is interested in the cellular and molecular mechanisms that control the developmental formation of the cerebral cortex. Our research is specifically focused on understanding how neural progenitors produce an enormous quantity and diversity of cortical during embryonic development and how abnormalities of neural progenitors lead to cortical malformations and neuropsychiatric disorders. We take advantage of human genetic mutations that are known to cause severe anatomical and functional deficits of the cerebral cortex, combining mouse genetic models of these human mutations with cell biology approaches to delineate the molecular mechanisms of developmental neurogenesis. Current research topics include neural progenitor cytoarchitecture maintenance, signal transduction, cell cycle regulation, and cell fate determination. We would like to learn how these cellular processes are interconnected spatiotemporally to govern the generation of diversified cortical neurons in normal and diseased conditions.

For more information, see Dr. Feng's faculty profile.

Publications

View Dr. Feng's full list of publications on PubMed.

Contact Us

Yuanyi Feng, PhD at 312-503-1046

Graduate Students

Shauna L. Houlihan
312-503-1119

Alison A. Lanctot
312-503-1119

Research Description

We investigate sensory organs and particularly the uniquely specialized cells that detect external signals (the sensory receptor cells) and communicate this information to the brain (the primary sensory neurons). Our approach is to identify and characterize novel genes involved in the formation (during development or regeneration), function (as sensory transducers), dysfunction and death (causing diseases like deafness or neuropathic pain) of these cells. The genes we have studied so far encode ion channels (of the Deg/ENaC and TRP families) and transcriptional regulators (zinc-finger proteins; these studied in collaboration with Anne Duggan). We are interested in all forms of sensation but, as of now, have primarily explored the somatic (touch and pain), auditory and nasal sensory organs.

Sensory Neuron Development: We found Insm1, a zinc-finger gene regulator that determines the number of olfactory receptor neurons. Insm1 is expressed in the olfactory epithelium, as it is everywhere else in the developing nervous system, in late (but not early) progenitors and nascent (but not mature) neurons, and it functions by promoting the transition of neuroepithelial progenitors from apical, proliferative and uncommitted (i.e., neural stem cells) to basal, terminally dividing and neuron-producing (Duggan et al., 2008; Rosenbaum, Duggan & García-Añoveros 2011). We are currently determining the role of Insm1 in other sensory organs, as well as elucidating the role of other novel neurodevelopmental genes.

Sensory Transduction: We pioneered a molecular model of how certain neurons can detect touch using DEG/ENaC channels and structural components of the extracellular matrix and the cytoskeleton (García-Añoveros et al., 1995; 1996), characterized a major pain transduction channel (TRPA1; Nagata et al., 2005), and continue searching for sensory transducers, particularly ion channels.

Sensory Neuron Degeneration: We found a form of cell death caused by mutations on ion channels that leave them open, generating lethal currents (García-Añoveros et al., 1998). In this way, we found how dominant mutations in the Mcoln3 (Trpml3) gene cause loss of mechanosensory cells of the inner ear and deafness (Nagata et al., 2008; Castiglioni et al., 2011). We continue exploring he role of TRPML3 and other ion channel in inner ear function and disease.

For more information, view the faculty profile of Jaime García-Añoveros, PhD or visit the Añoveros & Duggan lab site.

Publications

See Dr. García-Añoveros' publications on PubMed.

Staff Listing

Graduate Students

Chuan Foo
Teerawat Wiwatpanit

Post-doctoral Fellows

Jorge M. Cantú

Research Assistant Professor

Anne Duggan

Technical Staff

Freddie Márquez

Contact Info

Dr. García-Añoveros

Lab Phone: 312-503-4246
Office Phone: 312-503-4245

Research Description

The Kessler laboratory focuses on the biology of neural stem cells and growth factors and their potential for regenerating the damaged or diseased nervous system. A major interest of the laboratory has been the role of bone morphogenetic protein (BMP) signaling in both neurogenesis and gliogenesis and in regulating cell numbers in the developing nervous system.   Both multipotent neural stem cells and pluripotent embryonic stem cells are studied in the laboratory, and recent efforts have emphasized studies of human embryonic stem cells (hESC) and human induced pluripotent stem cells (hIPSC).  The Kessler lab oversees the Northwestern University ESC and IPSC core, and multiple collaborators use the facility. In addition to the studies of the basic biology of stem cells, the laboratory seeks to develop techniques for promoting neural repair in animal models of spinal cord injury and stroke.  In particular the lab is examining how stem cells and self-assembling peptide amphiphiles can be used together to accomplish neural repair. The lab is also using hIPSCs to model Alzheimer’s disease and other disorders. 

For more information see the faculty profile of John A Kessler, MD.

Publications

View Dr. Kessler's full list of publications in PubMed.

Contact

John Kessler, MD

Postdoctoral fellow jobs and graduate student rotation projects are available.

Research Description

SMA is characterized by the selective degeneration of spinal motor neurons. As the leading genetic cause of infant mortality, SMA affects one in every eight thousand live births. Our group is interested in studying mechanism regulating motor neuron development and function, as well as why motor neurons specifically degenerate in SMA. To address these questions, we use a combination of genetic, biochemical and cell biological approaches, and utilize genetically modified mice, induced pluripotent stem (iPS) cells reprogrammed from fibroblasts, and zebrafish as model systems. We focus on the regulation of mitochondrial functions in SMA pathogenesis. Based on our findings, we hope to develop new therapeutic strategies for treating SMA.

Dopaminergic neurons located in the ventral midbrain control movement, emotional behavior and reward mechanisms. Dysfunction of these neurons is implicated in Parkinson’s disease, drug addiction, depression and schizophrenia. Our group is interested in the genetic and epigenetic mechanisms regulating dopaminergic neuron functions in disease and aging conditions. We are particularly interested in how aging and mitochondrial oxidative stress contribute to dopaminergic neuron degeneration in Parkinson's disease through transcriptional and epigenetic regulations. We use mouse models, cultured neurons and iPS cells for these studies.

For more information visit Dr. Ma's faculty profile and  Dr. Ma's lab website within the Children's Hospital Research Center.

Publications

View Dr. Ma's publications at PubMed

Contact

Email Dr. Ma

Phone 773-755-6339

Lab Staff

Nimrod Miller, PhD, Postdoctoral Fellow

Han Shi, Graduate Student

Brittany Edens, Graduate Student

Kevin Park, Graduate Student

Monica Yang, Undergraduate Student

Aaron Zelikovich, Undergraduate Student

Research Description

The Oliver Lab focuses on understanding how each specific cell type and organ acquires all its specific and unique morphological and functional characteristics during embryogenesis. Alterations in the cellular and molecular mechanisms controlling organ formation can result in major defects and pathological alterations. Our rationale is that a better knowledge of the basic processes controlling normal organogenesis will facilitate our understanding of disease. Our goal is to dissect the specific stepwise molecular processes that make each organ unique and perfect. Our major research interests are the forebrain, visual system and the lymphatic vasculature and to address those questions we use a combination of animal models and 3D organ culture systems, stem cells and iPS cells.

Related to the lymphatic vasculature, our lab identified years ago the first specific marker for lymphatic endothelial cells and generated the first mouse model devoid of lymphatics. We have characterized many of the critical steps leading to the formation of the lymphatic vasculature. We have also reported that a defective lymphatic vasculature can cause obesity in mice and we are currently trying to determine whether this is also valid in humans.

In case of the central nervous system, our focus is to characterize how complex structures such as the forebrain and eye are formed. For that we have started to apply 3D organ culture systems derived from stem cell and iPS that allow us to grow eyes in a petri dish. Using this approach we expect to dissect the genes and mechanisms controlling these developmental processes.

For more information, visit Dr. Oliver’s faculty profile or visit the Guillermo Oliver Lab Site.

Publications

View Dr. Olivers's publications at PubMed

Contact

Email Dr. Oliver

Phone 312-503-1651

Research Description

Neurons communicate with each other at synapses, extremely specialized and plastic structures able to adjust both quantitatively and qualitatively to correctly respond to a changing environment. The majority of neuronal communication is mediated by the activation of glutamate receptors (GluRs), which triggers mechanisms able to induce changes at synaptic level that are thought to underlie higher cognitive functions. Accordingly, GluRs are extremely well regulated in a cell- and synapse-specific manner. Several mechanisms including the control of expression/degradation level, intracellular trafficking or channel properties work coordinately to regulate GluRs. Not surprisingly, an aberrant GluR trafficking and/or function is a shared hallmark for many neurological disorders, including Alzheimer’s disease, Huntington’s disease, schizophrenia and autism.

The Sanz-Clemente Lab is interested in the molecular mechanisms underlying GluR trafficking in normal and altered conditions. We use a multidisciplinary approach including biochemistry, cell and molecular biology, pharmacology as well as a variety of imaging techniques and the analysis of genetically-altered mouse lines for elucidating how GluRs are controlled during development, in response to experience or other stimuli and what is their impact on synaptic function. Similarly, we investigate how the dysregulation of these mechanisms lead to synaptic alterations and, eventually, to neurological disorders. Current research focuses on NMDA Receptor (NMDAR) regulation and its role in the pathogenesis of Alzheimer’s disease.

Recent Findings

The synaptic NMDAR subunit composition changes from predominantly GluN2B-containing to GluN2A-containing NMDARs during synaptic maturation and in response to activity and experience. This is an evolutionally conserved process that occurs in many brain areas and has important consequences in synaptic plasticity and intracellular signaling pathways.

• We have identified the phosphorylation within the GluN2B PDZ ligand by casein kinase 2 as a critical determinant for the NMDAR subunit switch, by promoting GluN2B internalization and allowing GluN2A insertion into synaptic sites.
• We have reported a novel structural role for CaMKII, acting as a scaffolding protein able to couple GluN2B and casein kinase 2 in response to activity, which controls NMDAR synaptic content.

Current Projects

• Investigating the molecular mechanisms controlling the balance between synaptic and extrasynaptic NMDARs and its role in the pathogenesis of Alzheimer’s disease
• Investigating the molecular mechanisms underlying synapse unsilencing during development
• Studying the differential reorganization of synaptic protein content by typical and atypical antipsychotic drugs

For lab information and more, see Dr. Antonio Sanz-Clemente's faculty profile and lab website.

Publications

See Dr. Sanz-Clemente's publications on PubMed.

Contact

Contact Dr. Sanz-Clemente at 312-503-4896.

Lab Staff

Postdoctoral Fellow

JieJie Wang, Luca Zangrandi 

Graduate Student

Andrew Chiu

Technical Staff

Levi Barse

Research Description

Animal development requires proper specification of different cell types and, at the same time, their organization in to multicellular arrangements such as tissues and organs. My laboratory investigates the mechanisms that control morphogenetic processes in vertebrate embryo. We are studying these processes in the zebrafish (Danio rerio) using a combination of genetic analysis with embryological and molecular methods. The transparency of zebrafish embryos together with the generation of fluorescent transgenic animals allows us to use high-resolution confocal microscopy for in vivo analysis of cell behaviors. Moreover, similarities in developmental programs among all vertebrates make zebrafish an excellent model for investigating human diseases and development.

We are focusing current efforts on the mechanisms that shape the zebrafish head skeleton. We are particularly interested in the role of non-canonical Wnt signaling in cartilage morphogenesis. Mutants with altered non-canonical Wnt signaling pathways exhibit similar cell behavior defects during gastrulation and cartilage morphogenesis. This observation led to the hypothesis that non-canonical Wnt signaling controls cartilage element morphology by modification of chondrocyte behavior. My work on the characterization of the zebrafish knypek gene has revealed a new role for glypicans (heparan sulfate proteoglycan) in controlling morphogenetic movements during gastrulation by promoting non-canonical Wnt11 signaling. We are investigating the function of non-canonical Wnts and their potential co-receptors, glypicans, in chondrocyte differentiation and polarization. Because the initial steps in craniofacial development are similar in all vertebrates, these studies will help understand genetic basis for relatively frequent congenital anomalies causing abnormal development of the hard and soft tissue of the head and neck.

We are also interested in the developmental roles of other glypicans, as these extracellular proteins can play an essential role by interaction with growth factors, chemokines, extracellular matrix proteins, enzymes and enzyme inhibitors. Glypicans can be involved in regulation of ligand-receptor interactions and control of ligand distribution, both within a tissue and on the cell surface. For example, the clinical features of Simpson-Golabi-Behmel overgrowth syndrome, caused by mutation in the gene encoding Glypican 3, suggest that this protein is involved in regulation of cell survival and/or proliferation. One goal of my laboratory is to identify zebrafish glypicans and characterize developmental processes that they are regulating.

For more information view Dr. Topczewski's faculty profile page

Publications

View Dr. Topczewski's publications at PubMed

Contact

Email Dr. Topczewski

Phone 773-755-6545

Lab Staff

Graduate Students

Rebecca Anderson

Left: Three rows of outer hair cells showing prestin proteins (green). Right: location of marshalin (green) in the organ of Corti, the mammalian hearing organ. Microtubule bundles (red) are stained with anti-a-tubulin.

Research Description

The goal of my lab is to identify and investigate molecules that play important roles in mammalian hearing, thus enriching our understanding of cochlear physiology and further developing a better strategy to prevent hearing loss. Deafness is commonly caused by defects in inner ear hair cells. In mammalian cochleae, inner hair cells (IHCs) function as sensory receptors conveying sound-related information to the central nervous system. Outer hair cells (OHCs) amplify the mechanical signals delivered to IHCs. The cooperation between IHCs and OHCs results in sensitive hearing and sharp tuning. Complex and sophisticated protein networks in hair cells facilitate their functions. Very often, genetic defects in a single protein can interfere with the entire network and cause deafness. Our research has been centered on several important proteins expressed in cochlea.

1. Molecular basis of cochlear amplification. OHCs undergo rapid somatic length changes when the voltage across their membrane is altered. This unique somatic electromotility provides the local mechanical amplification of the cochlear response to sound. Without OHCs, hearing threshold is elevated by 40-50 dB and frequency resolution deteriorates. Prestin is the motor protein of OHCs, and it is required for cochlear amplification (Zheng et al., Nature, 2000). Coincidently, prestin is only expressed in OHCs, which are also the most vulnerable cells in the organ of Corti. In the past, studying OHC amplification mechanisms and preventing OHC loss were considered two separate research fields. However, our recent data indicate a close connection between prestin's function and the vulnerability of OHCs to a variety of ototoxic exposures. To understand this link, we focus on investigating the molecular mechanism of the motor protein prestin using various cellular, biochemical and molecular biological methods.

2. Protein network of hair cells. We are focus on several deafness-related proteins: CDH23, CEACAM16 and Marshalin. Cadherin 23 is a tip-link protein of hair cells. CEACAM16 is an adhesive protein localized at the tectorial membrane (Zheng et al. PNAS, 2011). Marshalin is another newly identified microtubule minus-end binding protein that is expressed in the inner ear, and its expression is developmentally controlled (Zheng et al., Biology Open 2013). Very often, genetic defects in a single protein can interfere with the entire network and cause deafness. We are in the process of investigating interactions among these proteins and their physiological roles for normal hearing and deafness.

For more information, visit the faculty profile of Jing Zheng, PhD.

Publications

View Dr. Zheng's publications in PubMed

Contact

Phone 312-503-3417

Lab Staff

Research Associate

Satoe Humma

Research Technician

Vincent Mui