Kristen Kroll, PhD

Associate Professor of Developmental Biology

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Research interests

Our research focuses on defining gene regulatory networks (GRNs) that control neural cell specification, neurogenesis and the generation of specific neuronal cell types. We are particularly interested in understanding how epigenetic regulation modulates these networks and how their dysregulation contributes to neurodevelopmental disorders, including inherited epilepsies, autism spectrum disorder and neural tube defects.

This work uses directed differentiation of human pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells), mouse models and a wide range of cellular, molecular, and genomic approaches, to define roles for transcriptional and epigenetic regulation in shaping developmental transitions.

Gene regulatory networks in neural cell fate acquisition

Neural cell fate acquisition is mediated by transcription factors expressed in nascent neuroectoderm, including Geminin and members of the Zic transcription factor family. Recently, we identified chromatin association profiles for Geminin and Zic1 during neural fate acquisition at a genome-wide level (Sankar et al., 2016). We determined how Geminin deficiency affected histone acetylation at gene promoters during this process. We integrated these data to determine that Geminin associates with and promotes histone acetylation at neurodevelopmental genes, while Geminin and Zic1 bind a shared gene subset.

Geminin- and Zic1-associated genes exhibit embryonic nervous system-enriched expression and encode other regulators of neural development. Both Geminin and Zic1-associated peaks are enriched for Zic1 consensus binding motifs, while Zic1-bound peaks are also enriched for Sox3 motifs, suggesting co-regulatory potential. Accordingly, we found that Geminin and Zic1 could cooperatively activate the expression of several shared targets encoding transcription factors that control neurogenesis, neural plate patterning and neuronal differentiation.

We used these data to construct gene regulatory networks underlying neural cell fate acquisition. Establishment of this molecular program in nascent neuroectoderm directly links early neural cell fate acquisition with regulatory control of later neurodevelopment.
We are characterizing how disruption of this network contributes to the etiology of neural tube defects (NTDs) and other neurodevelopmental disorders.

Although NTDs are the second most common birth defect (~1:1000 fetuses and newborns), their causation is poorly understood. This is, in part, because NTD occurrence usually has a multi-factorial etiology, with both genetic and environmental susceptibility factors contributing to phenotypic manifestation and severity. Therefore, defining aspects of this regulatory network that are dysregulated to contribute to NTDs in multiple models may identify core processes that, when disrupted, increase NTD susceptibility.

This work also defined novel epigenetic regulators with likely roles in neural development, some of which we are functionally assessing in ongoing work.

Modeling human cortical interneuron development and dysregulation in neurodevelopmental disorders

Another major focus of our work is to identify transcriptional and epigenetic regulatory controls underlying the development of human cortical interneurons and to understand how their dysregulation contributes to neurodevelopmental disorders.

The mammalian cerebral cortex consists of two major types of neurons, excitatory glutamatergic projection neurons, that convey information to different regions of the brain, and GABAergic interneurons, that provide local inhibitory inputs to modulate responses of projection neurons and prevent over-excitation.

Imbalances between excitatory and inhibitory neuronal activities can emerge during cortical development. These imbalances often reduce inhibitory signaling through dysfunctional specification, migration, differentiation or survival of interneurons. Interneuron hypoplasia or dysfunction contributes to many neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder and intellectual disability syndromes.

We can now model gene regulatory networks that control human cortical interneuron specification and differentiation at a genome-wide level by generating mature interneurons from human pluripotent stem cells (embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). We are building gene regulatory networks underlying this process by integrating genome-wide binding profiles of key transcription factors and chromatin regulators, developmental transcriptome and epigenome changes, and effects of manipulating these activities.

This work has revealed new regulators of interneuron development, including transcriptional and chromatin modifying activities and non-coding RNAs, enriched in and/or involved in interneuron specification and differentiation.

After transplantation into the neonatal or adult nervous system, cortical interneurons have a striking ability to integrate into neural circuits and to provide inhibitory neuronal function in many locations, including their normal targets in the forebrain (hippocampus, cortex, striatum), as well as upon transplantation into heterologous locations such as the spinal cord. Because of this, transplanted mouse interneurons acquired from the medial ganglionic eminence have shown therapeutic utility in treating disease in mouse models of epilepsy, Parkinson’s disease, chronic pain, schizophrenia and anxiety.

We are currently applying this approach with in vitro differentiated human interneurons, to assess their capacity to engraft and migrate to target locations in the murine brain, and to suppress seizures in a murine model of temporal lobe epilepsy. These approaches can be used to determine how interneuron differentiation or maturation state, or subtype identity, contributes to capacity to engraft, migrate and ameliorate disease phenotypes.

We have also defined genes with interneuron-enriched expression whose mutation contributes to human neurodevelopmental disorders, including inherited epilepsies and autism spectrum disorder.

In collaboration with the Intellectual and Developmental Disability Research Center, we are deriving iPSCs from epilepsy and autism patients with mutations in some of these genes and are performing directed differentiation into cortical excitatory and inhibitory neurons and cerebral organoids. These are subjected to a battery of assays to define developmental, cellular, molecular and functional abnormalities that contribute to the disorder.

We can use these models to assess the relative contributions of genetic background versus pathogenic mutations, by comparisons of isogenic neurons with versus without engineered correction of mutations.

We are also using these models to assess how differential expressivity of a disorder among family members carrying a known pathogenic mutation manifests in cellular, molecular, and functional differences between neurons from these family members.

Epigenetic regulation in pediatric glioblastoma

Dysregulation of the epigenome is also an important but incompletely characterized aspect of tumorigenesis in pediatric glioblastoma (GBM). Malignant gliomas of early childhood frequently carry heterozygous histone H3.3 lysine 27 to methionine (H3K27M) mutations, while those tumors without H3K27M mutations carry mutations in other genes encoding epigenetic regulatory activities that control H3 modification.

Polycomb-mediated repressive H3K27 methylation critically controls gene expression and cell state to maintain normal neural and glial stem and progenitor cells and mutation of this histone residue drives pediatric GBM tumorigenesis through incompletely understood mechanisms. Therefore, we are working collaboratively to define epigenetic activities required to maintain the stem cell-like tumor initiating and propagating properties of pediatric and adult GBM versus those involved in maintenance of normal neural and glial stem and progenitor cells.

Comparing requirements for epigenetic regulatory activities across these distinct cell contexts will enable us to better understand differences in the biology of tumorigenesis in pediatric versus adult GBM and to identify novel targets for therapeutic intervention.

Emily Lewis, Kristen Kroll, Kesavan Meganathan, Ramachandran Prakasam


1988 B.A. Northwestern University, Evanston, IL

1994 Ph.D. University of California, Berkeley, California

Academic Positions

1988-94 Dept. of Molecular and Cell Biology University of California at Berkeley

1994-2000 Postdoctoral Fellow with Marc W. Kirschner, Professor and Chair Dept. of Cell Biology, Harvard Medical School, Boston, MA

1998 Independent consultant, Genetics Institute, Cambridge, MA

2000- Assistant Professor, Washington University School of Medicine, Dept. of Molecular Biology and Pharmacology

2007-Associate Professor, Washington University School of Medicine, Dept. of Molecular Biology and Pharmacology


2007 Hope Award, American Cancer Society, Wash. U. School of Medicine

2006 American Cancer Society Research Scholar, Wash. U. School of Medicine

2000-02 Basil O’Connor Research Award, March of Dimes, Wash. U. School of Medicine

2000-02 Howard Hughes Medical Institute, Faculty Development-Basic Research Award, Wash. U. School of Medicine

1995-98 Postdoctoral Fellowship, Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation, Harvard Medical School

1992 Teaching Effectiveness Award, UC Berkeley

1992 Outstanding Graduate Student Instructor, UC Berkeley 1988 Phi Beta Kappa, Northwestern University

1987 Phi Eta Sigma honorary society member, Northwestern University

1987 National Science Foundation Undergraduate Research Fellowship, Northwestern University

1986-87 Alice G. Hough Scholarship, Northwestern University

Selected publications

See a complete list of Dr. Kroll’s publications »