Kristen L. Kroll, Ph.D.

Developmental Biology

Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Neurosciences Program

  • 314-362-7045

  • 314-747-5519

  • 314-362-7058

  • 320 McDonnell Medical Sciences Building



  • human pluripotent stem cell, autism, neurodevelopmental disorders, cerebral organoid, epigenetic regulation, neurobiology, embryonic stem cell, neural stem cell, transcription, gene regulatory network, chromatin, embryo

  • Transcriptional and epigenetic regulation of neural development and its dysregulation to cause neurodevelopmental disorders

Research Abstract:

Our research focuses on defining gene regulatory networks 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 autism spectrum disorder. This work uses directed differentiation of human 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.

Our main research interests are outlined below (also see our website

A. Modeling Neurodevelopmental Disorders in Human Pluripotent Stem Cell-Derived Neurons and Organoids.

Human cellular models play a central role in functional genomic research to define the basis of neurodevelopmental disorders: lack of experimental access to the developing human brain precludes direct study and many disorders cannot be recapitulated in animal models, due to species-specific features of the human genome sequence and neurodevelopmental programs. My laboratory currently leads several efforts at Washington University School of Medicine (WU) to characterize how pathogenic gene variants contribute to intellectual and developmental disabilities (IDDs) in patient-derived induced pluripotent stem cell (iPSC) models;

We lead the Cellular Models program for WU’s Intellectual and Developmental Disabilities Research Center (IDDRC), coordinating with the IDDRC’s Clinical-Translational Core to build patient-derived cellular models of IDDs. We also coordinate human cell and organoid-based modeling under PreMIER, WU’s model organism screening platform for precision medicine; PreMIER links WU clinicians and patients with optimal models for defining mechanisms of disease. I also co-lead the NICHD-supported Cross-IDDRC Human Cellular Models Group, which engages the 14 IDDRCs in the United States in collaborative efforts to build and share human IDD cellular models, develop cross-IDDRC calibrated platforms for human cellular modeling, perform data meta-analyses, and develop IDD model bio- and data-repositories models as resources for the network.

Ongoing modeling projects are listed below:

1) Mechanisms by which pathogenic CHD2 mutations cause neurodevelopmental disorders. In work supported by NINDS, we are using stem cell models from patients with pathogenic mutations in CHD2 and other resources to characterize the genome-wide binding profile of CHD2 during human neuronal differentiation, define mechanisms by which CHD2 regulates the epigenome, and to determine how these programs are altered by pathogenic CHD2 mutations that cause autism and/or epilepsy.

2) Genomic and functional characterization of ASD and ID-associated MYT1L mutation. In work supported by NIMH, the WUSTL IDDRC, and the Jakob Gene Fund, we are characterizing the consequences of pathogenic MYT1L mutation on neurodevelopment and function in iPSC and mouse models.

3) Using human pluripotent stem cell models to evaluate pathogenicity and define disease mechanisms for a ZNF292 variant found in UDN373964. In work supported by the NIH Common Fund/NINDS, we are defining the pathogenicity and phenotypic consequences of a ZNF292 variant present in a patient in the Undiagnosed Diseases Network. We have also initiated efforts to model additional ZNF292 pathogenic variants present in this patient population and to characterize mouse models of Znf292 deficiency.

4) Modeling differential cognitive function in Down Syndrome in human pluripotent stem cell models. In work supported by the NICHD, we are deriving and characterizing new iPSC models of Down Syndrome from deeply phenotyped, cognitively stratified individuals, to identify contributors to differential cognitive function in this patient population.

5) Cellular Models Program, IDDRC. In work supported by the NICHD (WUSTL IDDRC), we are building and characterizing several new types of iPSC models of neurodevelopmental disorders in collaboration with John Constantino and Chris Gurnett. Prior IDDRC support underpinned our modeling efforts focused on identifying the basis of differential clinical phenotypic penetrance in multiplex ASD pedigrees.

6) Establishing novel stem cell platforms to model developmental disorders in children. In work supported by the Children’s Discovery Institute, and in collaboration with Thor Theunissen and Lila Solnica-Krezel, we are defining how transitions between stem cell states are regulated and using new stem cell models to study pediatric disease.

7) Modeling brain overgrowth disorders. In work supported by the M-CM Network and Engelhart Family Foundation, we are deriving new models of brain overgrowth disorders from individuals with PIK3CA or AKT3 mutation.

B. Transcriptional and epigenetic regulation of cortical development. A 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. Accordingly, altered interneuron development contributes to many neurological disorders, including epilepsy, schizophrenia, autism spectrum disorder, and intellectual disability syndromes.

We are modeling 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 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.

We have also defined genes with interneuron-enriched expression whose mutation contributes to human neurodevelopmental disorders, including inherited epilepsies and autism spectrum disorder. We are deriving iPSCs from epilepsy and autism patients with mutations in some of these genes. These are subjected to a battery of assays to define developmental, cellular, molecular, and functional abnormalities that contribute to the disorder.

Mentorship and Commitment to Diversity Statement:
Please see the mentoring statement on our lab's website.

Selected Publications:

For a current list of our publications, please see:

Meganathan K., Prakasam R., Gontarz P., Zhang B., Baldridge D., Bonni A., Urano F., Huettner J.E., Constantino J.N., Kroll K.L. Alterations in neuronal physiology, development and function associated with a common duplication of chromosome 15 involving CHRNA7. BMC Biology 2021.

Anderson NC, Chen PF, Meganathan K, Afshar Saber W, Bhattacharyya A#, Kroll K#, and Sahin M#, on behalf of the Cross-IDDRC Human Stem Cell Working Group. Balancing serendipity and reproducibility: pluripotent stem cells as experimental systems for intellectual and developmental disorders. #: Corresponding authors. Stem Cell Reports 2021 8:16(6):1446-1457.

Lewis EMA, Sandoval L, Kaushik K, Dietmann S, Kroll KL. Epigenetic regulation during human cortical development: seq-ing answers from the brain to the organoid. Invited review for Neurochemistry International Special Issue: Epigenetic regulation of nervous system development and function. Eds. MacDonald J, Tharin S, Hall S. Neurochem Int. 2021 147:105039

Kroll KL. New models to understand the intricacies of neurodevelopmental disorders”. Scientia

Lewis, EMA, Sankar, S, Tong, C, Patterson, ES, Waller, LE, Gontarz, P, Zhang, B, Ornitz, DM, Kroll, KL. Geminin is required for Hox gene regulation to pattern the developing limb. Dev Biol., 2020, 464(1):11-23.

Lewis, EMA, Meganathan, K, Baldridge, D, Gontarz, P, Zhang, B, Bonni, A, Constantino, JN, and Kroll, KL. Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons. Molecular Autism, 2019, 10, 51

Lewis EMA. and Kroll KL. Development and disease in a dish: the epigenetics of neurodevelopmental disorders. Epigenomics, 2018, Jan 15.

Meganathan K, Lewis MA, Gontarz P, Liu S, Stanley EG, Elefanty AG, Huettner JE, Zhang B, and Kroll KL. Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. Proc. Natl. Acad. of Sciences, 2017; 114(52):E11180-E11189.

Sankar S, Patterson ES, Lewis E, Waller LE, Tong C, Dearborn J, Wozniak D, Rubin J, and Kroll KL. Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors. Genes and Cancer, 2017 8(9-10):725-744.

Zhang B, Madden P, Sankar S, Flynn J, Gu J, Xing X, Kroll KL, Wang T. Uncovering the transcriptomic and epigenomic landscape of nicotinic receptor genes in non-neuronal tissues. BMC Genomics, 2017; 18(1):439. doi: 10.1186/s12864-017-3813-4

Sankar S, Yellajoshyula D, Zhang B, Teets B, Rockweiler N, Kroll KL. Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1. Scientific Reports, 2016; 6:37412.

Dandulakis MG, Meganathan K, Kroll KL, Bonni A, and Constantino JN. Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research. Journal of neurodevelopmental disorders. 2016 8:22.

Corley M, Kroll KL. The roles and regulation of Polycomb complexes in neural development. Cell Tissue Res. 2015 Jan;359(1):65-85.

Patterson ES, Waller LE, Kroll KL. Geminin loss causes neural tube defects through disrupted progenitor specification and neuronal differentiation. Dev Biol. 2014 Sep 1;393(1):44-56.

Caronna EA, Patterson ES, Hummert PM, Kroll KL. Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression. Stem Cells. 2013 Aug;31(8):1477-87.

Siles L, Sánchez-Tilló E, Lim JW, Darling DS, Kroll KL, Postigo A. ZEB1 imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression. Mol Cell Biol. 2013 Apr;33(7):1368-82.

Yellajoshyula D, Lim JW, Thompson DM Jr, Witt JS, Patterson ES, Kroll KL. Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis. Mol Cell Biol. 2012 Nov;32(22):4549-60.

Sengupta R, Dubuc A, Ward S, Yang L, Northcott P, Woerner B, Kroll K, Luo J, Wechsler-Reya R, Rubin J. CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma. Cancer Res. 2012 Jan 1;72(1):122-32.

He Z, Cai J, Lim JW, Kroll K, Ma L. A novel KRAB domain-containing zinc finger transcription factor ZNF431 directly represses Patched1 transcription. J Biol Chem. 2011 Mar 4;286(9):7279-89.

Yellajoshyula D, Patterson ES, Elitt MS, Kroll KL. Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state. Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3294-9.

Lim JW, Hummert P, Mills JC, Kroll KL. Geminin cooperates with Polycomb to restrain multi-lineage commitment in the early embryo. Development. 2011 Jan;138(1):33-44.

Langer EM, Feng Y, Zhaoyuan H, Rauscher FJ 3rd, Kroll KL, Longmore, GD. Ajuba LIM proteins are snail/slug corepressors required for neural crest development in Xenopus. Dev Cell. 2008 Mar;14(3):424-36.

Seo S, Lim JW, Yellajoshyula D, Chang LW, Kroll KL. Neurogenin and NeuroD direct transcriptional targets and their regulatory enhancers. EMBO J. 2007 Dec 12;26(24):5093-108.

Lauberth SM, Bilyeu AC, Firulli BA, Kroll KL, Rauchman M. A phosphomimetic mutation in the Sall1 repression motif disrupts recruitment of the nucleosome remodeling and deacetylase complex and repression of Gbx2. J Biol Chem. 2007 Nov 30;282(48):34858-68.

Kroll KL. Geminin in embryonic development: coordinating transcription and the cell cycle during differentiation. Front Biosci. 2007 Jan 1;12:1395-409.

Boos A, Lee A, Thompson DM, Kroll KL. Subcellular translocation signals regulate Geminin activity during embryonic development. Biol Cell. 2006 Jun;98(6):363-75.

Seo S, Kroll KL. Geminin`s double life: chromatin connections that regulate transcription at the transition from proliferation to differentiation. Cell Cycle. 2006 Feb;5(4):374-9. PubMed PMID: 16479171

Taylor JJ, Wang T, Kroll KL. Tcf- and Vent-binding sites regulate neural-specific geminin expression in the gastrula embryo. Dev Biol. 2006 Jan 15;289(2):494-506.

Seo S, Herr A, Lim JW, Richardson GA, Richardson H, Kroll, KL. Geminin regulates neuronal differentiation by antagonizing Brg1 activity. Genes Dev. 2005 Jul 15;19(14):1723-34.

Seo S, Richardson GA, Kroll KL. The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD. Development. 2005 Jan;132(1):105-15.

Last Updated: 7/2/2021 8:02:41 PM

Figure 1. Genome-wide binding profiles for Geminin and Zic1 were used to define gene regulatory networks in neural cell fate acquisition. (A-D) Comparison of Gmnn-associated and Zic1-associated genes in NE. (A) A subset of genes is associated with both Gmnn and Zic1. p-value (Chi-square test with Yates’ correction) < 2.2X10-16. (B) z-scores for enrichment of expression in ES versus CNS tissues for all Zic and/or Gmnn associated genes. (C) Comparison of all Gmnn or Zic1 associated genes, subsets that undergo Gmnn-dependent acetylation, and transcription factors, with their relative enrichment of expression in embryonic CNS tissues. (D) GO enrichment analysis for associated genes with increased versus decreased expression in embryonic CNS, relative to ES cells. (E) Gene regulatory networks in neural cell fate acquisition. Gmnn- and Zic1-associated genes in NE that encode transcription factors and epigenetic regulatory activities were assessed for co-association with Sox2 and Sox3 in ES-derived NE (see text). The set of these genes that exhibit CNS-enriched expression (>two-fold greater expression in E14 CNS, relative to ES cells), and were associated with Gmnn and/or Zic1 plus Sox2 and/or Sox3 were used to build gene regulatory networks showing associations. Figure 2. Human cortical interneuron derivation and characterization. (A) Immunocytochemistry (ICC) for ventral telencephalic/MGE, neuron, cIN and alternate cell fate (RAX/DARPP32) markers, in day 35 hESC-derived interneurons (scale bar=100µm). (B) FACs for Nkx2-1 and (C) quantitation of % ICC+ cells. Inset: FACS analysis for the SST+ cortical interneuron subtype. (D) Synapsin-GFP expressing day 35 cIN (after PSA-NCAM+ selection; scale bar=100µM) were (E) transplanted into the cortex of P2 NOD/SCID mice (20 days post-transplantation shown; B’ box in B, scale bar=100µM) or (F) transplanted into the hippocampus (CA3) of NOD/SCID adult mice (1 month post-transplantation shown, C’ box in C; scale bar=50µM). (D-E) Representative action potential firing pattern (G) evoked by injection of a square pulse, (H) spontaneous. (I) Voltage-gated currents evoked by a step from -80 to +50 mV in the absence (black) or presence (red) of the sodium channel antagonist tetrodotoxin (TTX, 0.5 µM). (J) Spontaneous synaptic currents recorded at -20 and -80 mV. Exposure to the GABAA receptor antagonist bicuculline methiodide (200 µM), indicated by the open box above each trace, blocked spontaneous Inhibitory postsynaptic currents (IPSCs). IPSCs were inward at -80 mV and outward at -20 mV, consistent with the equilibrium potential for chloride (-54 mV) with our internal and external solutions. Work performed in collaboration with Jim Huettner’s laboratory
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