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Anthony Koleske, PhD

Ensign Professor of Molecular Biophysics and Biochemistry and of Neuroscience
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About

Titles

Ensign Professor of Molecular Biophysics and Biochemistry and of Neuroscience

Deputy Dean for Research, (Basic Science)

Biography

Anthony J. Koleske is an expert in understanding the biochemical mechanisms that regulate neuronal dendrite and synapse development. After receiving a B.S. in Biochemistry and Molecular Biology at the University of Wisconsin-Madison, Dr. Koleske performed his Ph.D. studies with Dr. Richard Young at the Whitehead Institute/Massachusetts Institute of Technology. For his Ph.D. thesis, Dr. Koleske discovered the RNA polymerase II holoenzyme, an important advancement in understanding how gene transcription is turned on. Dr. Koleske went on to do a postdoctoral fellowship with Dr. David Baltimore at M.I.T., where he began his work studying cellular functions of Abl family kinases, which his laboratory has shown are essential regulators of the cytoskeleton in diverse cell types. Dr. Koleske joined the Department of Molecular Biophysics and Biochemistry at Yale University in 1998, where he currently is Professor and holds a joint appointment in the Department of Neuroscience. Dr. Koleske is the recipient of numerous awards including a Jane Coffin Childs Postdoctoral Fellowship, Special Fellowship and Scholar Awards from the Leukemia and Lymphoma Society, Young Investigator and Established Investigator Awards from NARSAD, an Established Investigator Award from the American Heart Association. He has served widely on review panels, including terms as Chair of the Basic Science Study Section for the American Heart Association and the Neurodifferentiation, Plasticity, Repair, and Rhythmicity Study Section of the NIH. He served as Director of the combined PhD programs in the Biological and Biomedical Sciences at Yale (2014-2019). He also served Director of the China Scholarship Council-Yale World Scholars Program (2014-2019) and was a co-Director of the Yale BioMed SURF Amgen Scholars Program (w/Faye Rogers and Barbara Kazmierczak)(2015-2020).

Appointments

Education & Training

PhD
Massachusetts Institute of Technology (1993)
BS
University of Wisconsin (1988)

Research

Overview

Recent advances from scientists in the Koleske Lab:

A key trigger for synapse maturation

Synapses in the developing brain are structurally dynamic but become stable by early adulthood. INP Student Mitch Omar discovered that an extracellular matrix molecule called laminin α5 stabilizes synapses during this developmental transition and we elucidated key cellular and molecular mechanisms by which it acts. See our paper in Cell Reports: https://www.cell.com/cell-reports/fulltext/S2211-1247(17)31460-2.

Press Releases:

https://www.ninds.nih.gov/News-Events/News-and-Press-Releases/Press-Releases/Study-identifies-protein-important-brain

https://scitechdaily.com/laminin-alpha-5-is-crucial-to-adolescent-brain-maturation/

https://news.yale.edu/2017/10/31/maturity-molecule-helps-adolescent-brain-grow

https://neurosciencenews.com/laminin-alpha-5-neurodevelopment-7854/

Stabilization of actin filaments by Abl2 and cortactin.

The actin-binding protein cortactin promotes the formation and maintenance of actin-rich structures, including lamellipodial protrusions in fibroblasts and neuronal dendritic spines. Cortactin cellular functions have been attributed to its activation of the Arp2/3 complex, which stimulates actin branch nucleation, and to its ability to recruit regulators of Rho family GTPases. Cortactin also binds actin filaments and slows filament depolymerization, but the mechanism by which it does so, and the relationship between actin binding and stabilization, is unclear. Using a combination of in vitro biochemical assays and total internal reflection fluorescence microscopy to measure rates of single filament actin depolymerization, Cell Biology student Alex Scherer defined the key cortactin-actin interactions are necessary and sufficient to stabilize actin filaments. Our ongoing work is using structural methods to obtain a high-resolution perspective of the cortactin:actin complexes and using FRAP and super-resolution approaches to understand how alteration of cortactin impacts actin structure and dynamics in dendritic spines. MB&B student Josie Bircher is using similar strategies and cryo-EM to understand how the Abl2 tyrosine kinase interacts with cortactin to regulate actin stability.

See our papers in:

the Journal of Biological Chemistry: https://www.ncbi.nlm.nih.gov/pubmed/25540195; https://www.ncbi.nlm.nih.gov/pubmed/29929984;

Science Reports: https://www.ncbi.nlm.nih.gov/pubmed/29196701;

and the Journal of Neuroscience; https://www.ncbi.nlm.nih.gov/pubmed/23365224

Mutations in Trio cause autism, schizophrenia, and related disorders.

Bipolar disorder, schizophrenia, autism, and intellectual disability are complex neurodevelopmental disorders, debilitating millions of people. Therapeutic progress is limited by poor understanding of underlying molecular pathways. Using a targeted search, we identified an enrichment of de novo mutations in the gene encoding the 330-kDa triple functional domain (TRIO) protein associated with neurodevelopmental disorders. TRIO contains two guanine nucleotide exchange factor (GEF) domains with distinct specificities. In collaboration with the Mains and Eipper groups at UConn, INP student Sara Katrancha discovered that genetic damage to both TGEF domains altered TRIO catalytic activity, decreasing TGEF1 activity and increasing TGEF2 activity. In ongoing work, we are using CRISPR/Cas9 technology to create mice with human TRIO mutations to help us discover the mechanisms by which disruption of TRIO function impairs brain development and function. See our papers in Human Molecular Genetics: https://www.ncbi.nlm.nih.gov/pubmed/28973398, and Cell Reports: https://www.ncbi.nlm.nih.gov/pubmed/30840899 and press releases (https://news.yale.edu/2019/03/05/single-gene-linked-host-abnormalities-during-neurodevelopment; https://medicalxpress.com/news/2019-03-gene-linked-host-abnormalities-neurodevelopment.html; https://epilepsyu.com/single-gene-linked-to-host-of-abnormalities-during-neurodevelopment/)

NMDA receptor dysfunction as a cause of cognitive impairment in Noonan Syndrome.

Hyperactivating mutations in the non-receptor tyrosine phosphatase SHP2 cause Noonan syndrome (NS). NS is associated with cognitive deficits, but how hyperactivation of SHP2 in NS changes neuron function was not well understood. INP student Aaron Levy found that SHP2 uncouples the NMDA receptor to from the cytoskeletal adaptor protein Nck1 and this reduces NMDA receptor transmission, synaptic plasticity, and causes learning and memory defects. Look for our recent paper in press at Cell Reports https://www.ncbi.nlm.nih.gov/pubmed/30089263

Control of MT elongation by Abl2.

Abl family kinases are essential regulators of cell shape and movement. Genetic studies revealed functional interactions between Abl kinases and microtubules, but the mechanism by which Abl family kinases regulate microtubules (MTs) remains unclear. Here, we report that Abl2 directly binds to MTs and regulates MT behaviors. Abl2 uses it C-terminal half to bind MTs, mediated in part through electrostatic binding to tubulin C-terminal tails. Using purified proteins, we found that Abl2 stably binds the MT lattice and promotes MT polymerization and stability. In cells, knockout of Abl2 significantly impairs MT growth and this defect can be rescued via re-expression of Abl2 or an Abl2 fragment containing MT-binding regions. These results show Abl2 uses its C-terminus to bind MTs and directly regulate MT dynamics. Look for upcoming papers by Cell Biology student Yuhan Hu and MB&B student Wanqing Lyu from our lab.

Diversity and Inclusion

Our group is composed of individuals from diverse scientific and personal backgrounds who bring their talents, willingness to strive, and work ethic to all of our professional and social activities. We are committed to treating each other with respect, dignity, fairness, caring, equality, to help build and maintain each other’s self-esteem, and to support each other in our collective achievements.

Mentoring Policy

Our goal is to mentor students to develop their relevant scientific and laboratory skills as well as other vital career skills required to succeed in diverse careers. I support students in my lab pursuing career training activities (e.g. teaching, writing) outside of lab. I have completed training from the National Research in Mentoring Network curriculum and have had many leadership positions in graduate education. The average time for PhD in our lab is just over 5 years. PhD trainees in our lab win awards and go on to distinguished careers at Yale and beyond.

Medical Subject Headings (MeSH)

Biochemistry; Biophysics; Molecular Biology; Morphogenesis; Schizophrenia; Stress, Physiological

Research at a Glance

Yale Co-Authors

Frequent collaborators of Anthony Koleske's published research.

Publications

2024

2023

2022

2021

Get In Touch

Contacts

Academic Office Number
Lab Number
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Mailing Address

Molecular Biophysics and Biochemistry

PO Box 208024, 333 Cedar Street

New Haven, CT 06520-8024

United States

Administrative Support