Positions

Professor
Molecular and Human Genetics
Baylor College of Medicine
Investigator
Howard Hughes Medical Institute
Director
Jan and Dan Duncan Neurological Research Institute
Texas Children’s Hospital
Professor
Pediatrics - Neurology and Developmental Neuroscience
Baylor College of Medicine
Professor
Neuroscience
Baylor College of Medicine
Professor
Program in Integrative Molecular and Biomedical Sciences
Baylor College of Medicine
Professor
Program in Developmental Biology
Baylor College of Medicine
Professor
Program in Translational Biology & Molecular Medicine
Baylor College of Medicine
Ralph D. Feigin, M.D. Endowed Chair
Baylor College of Medicine
Houston, Texas, United States

Education

Post-Doctoral Fellowship at Baylor College Of Medicine
MD from Meharry Medical College
BS from American University Of Beirut

Certifications

General Pediatrics
American Board of Pediatrics

Honors & Awards

Honorary Doctorate of Science
March of Dimes Prize in Developmental Biology
Sckolnick Prize
The Pearl Meister Greengard Prize
Dickson Prize in Medicine
Gruber Prize in Neuroscience
International Rett Syndrome Foundation's Circle of Angels Research Award
Vilcek Prize for Biomedical Research
National Academy of Sciences
Elected
Institute of Medicine, National Academy of Sciences
Elected
Texas Women's Hall of Fame Award
Texas Governor's Commission for Women
Bernard Sachs Award
Child Neurology Society
Sidney Carter Award
American Academy of Neurology
Soriano Award
The American Neurological Association
Javits Award
NINDS Council, National Institutes of Health
E. Mead Johnson Award
Society of Pediatric Research
Kilby Award for Extraordinary Contributions to Society
Bristol-Myers Squibb Neuroscience Distinguished Achievement Award
Marion Spencer Fay Award
Drexel University College of Medicine
Robert J. and Claire Pasarow Foundation Award in Neuropsychiatry
Neuronal Plasticity Prize
IPSEN Foundation
Marta Philipson Award in Pediatrics
Philipson Foundation for Research
Honorary Doctorate of Science
Meharry Medical School
Honorary Doctorate of Science
Middlebury College

Professional Interests

  • Pathogenesis of neurodegenerative disease
  • Rett syndrome
  • Normal neurodevelopment
  • Ataxin-1
  • Akt
  • Mouse models

Professional Statement

My laboratory uses genetic, behavioral and cell biological approaches to explore the pathogenesis of polyglutamine neurodegenerative diseases and Rett syndrome, and to study normal neurodevelopment.

Several dominantly inherited spinocerebellar ataxias (SCAs) are caused by expansion of a CAG repeat that encodes glutamine (Q). We discovered that ataxin-1 (ATXN1) with an expanded glutamine tract accumulates in neurons of patients and mouse models of SCA1 and redistributes components of the protein folding and degradation machinery. Surprisingly, genetic studies in Drosophila and mice showed that high levels of even wild-type (WT) ATXN1 can produce effects similar to mutant ATXN1. We hypothesized that ATXN1 exists in alternate conformations, and that the expanded glutamine tract favors a conformation that resists degradation and alters the interactions of ATXN1 with its normal protein partners. With our collaborators, we identified a number of ATXN1 interactors and showed that the expanded polyglutamine tract interferes with the functions of these ATXN1-partner complexes in vivo in various ways. For example, mutant ATXN1 must be in its large native complexes with the transcription repressor Capicua (CIC) to cause neurodegeneration and that decreasing CIC levels by 50% rescues many SCA1 phenotypes in mice (Fryer 2012). Furthermore, we found that partial reduction of ATXN1 levels by mere 20% also rescues several phenotypes (Jafar-Nejad et al., 2011). These data led us to embark on parallel forward genetic screens in human cells and in the Drosophila SCA1 model to identify genes whose inhibition reduces ATXN1 levels and toxicity (Park et al., 2013). The screens identified multiple components of the RAS/MAPK/MSK1 pathway as modulators of ATXN1 levels. The success of this strategy inspired us to employ it to screen for modulators of APP, tau, and α-synuclein proteins, where the protein levels are crucial in the development of Alzheimer and Parkinson diseases, respectively. Beyond these efforts, we are focusing on understanding the in vivo functions of ATXN1, its paralog ATXN1L, and interactors CIC and RBM17 using a combination of genetic studies and molecular analyses.

We discovered that mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2) cause Rett syndrome (Amir, 1999), an incapacitating, progressive postnatal-onset disorder that affects cognitive, language, emotional, and motor skills. We and others have since discovered that MECP2 mutations also underlie autism, various forms of retardation ranging from mild to severe, and even early-onset psychosis. To better understand the role of MeCP2 in Rett pathogenesis, we generated a mouse model using a mutation that causes a typical Rett phenotype in humans, and we also generated mice that overexpress MECP2 at twice the normal levels. The latter mice also develop a progressive neurodevelopmental disorder, which led us back to the clinic to discover a parallel syndrome in human children who have duplications or triplications spanning MECP2.

We next embarked on a series of studies in which we deleted Mecp2 in specific neuronal groups to understand the genesis of different aspects of the wide-ranging Rett phenotype. To our surprise, removing MeCP2 from GABAergic neurons alone reproduced most of the features of RTT, from altered social behavior and seizures to incoordination and stereotyped forepaw movements (Chao, 2010). Interestingly, deletion of Mecp2 in adult mice reproduces all features of the germline deletion mice, including the delayed onset of symptoms and death (McGraw, 2011).

More recently we turned to human data and used genotype-phenotype correlations to identify key functional domains of the protein. The first of theses studies showed MeCP2 is evolutionarily related to HMGA1 protein and that an AT-hook domain in its C-terminus is a key determinant of disease severity (Baker 2013). We are now seeking to understand how MeCP2 affects chromatin architecture, studying the effects of loss or gain of MeCP2 on network activity, and testing therapeutics that enhance GABA signaling in Rett mouse models.

My lab identified Math1 (mouse atonal homolog 1, also known as Atoh1), and showed that it is essential for the genesis of a wide range of cell types, including cerebellar granule neurons, spinal cord interneurons, inner ear hair cells, (Bermingham, 1999), and intestinal secretory (paneth, goblet, and enteroendocrine) cells. Math1 redefines the rhombic lip and its derivations, and Math1-dependent neurons are critical for conscious and unconscious proprioception and for perinatal breathing (Rose, Neuron 2009; Rose, PNAS 2009). In vivo genetic interaction studies identified Math1 as a critical factor for the development of sonic hedgehog induced medulloblastoma (Flora, 2009).

Most recently, we have delineated the role of Math1 in the retrotrapezoid nucleus neurons and the importance of these cells for neonatal respiration and CO2 chemosensitivity. Ongoing studies are focusing on identifying other components of the respiratory hindbrain neurons that are Math1/Atoh1 dependent and on elucidating the molecular functions of Math1 by identifying its interactors and targets in different cellular contexts.

Selected Publications