Kristen Kroll

Last updated
Kristen L. Kroll
Alma mater
Known forTranscriptional and epigenetic regulation of brain development
Scientific career
Fields Developmental biology, Neuroscience, Transcription, Epigenetics
Institutions Washington University School of Medicine

Kristen Kroll is an American developmental and stem cell biologist and Professor of Developmental Biology at Washington University School of Medicine. Her laboratory studies transcriptional and epigenetic regulation of brain development and its disruption to cause neurodevelopmental disorders. [2] [3] [4]

Contents

Early life and education

Kroll grew up in Wisconsin. She graduated from Wilmot High School in 1984 and received her Bachelor's Degree with the highest honors from Northwestern University in 1988. [5] [6] [7] She became interested in a career in developmental biology while doing undergraduate research in the laboratory of Robert Holmgren, where her project involved cloning the segment polarity gene Cubitus interruptus, a Drosophila homolog of the GLI transcription factors that mediate Hedgehog signaling. [5]

Career

In her doctoral work in John Gerhart's lab at the University of California at Berkeley, Kroll developed nuclear transplantation-based approaches for transgenesis in embryos of the frog Xenopus laevis . [5] In collaboration with Dr. Enrique Amaya, she used nuclear transfer-based transgenesis to directly produce animals with stable transgene integration in each cell without breeding. [8] [9] This work expanded the utility of Xenopus for studying vertebrate embryogenesis, enabling high throughput analysis of cis-regulatory elements and the study of later aspects of development, during which gene function could not previously be manipulated. [10] [11] [12] [13] [14]

As a Damon Runyon-Walter Winchell Foundation Postdoctoral Fellow, Kroll pursued an interest in developmental biology during postdoctoral work in Marc Kirschner's lab at Harvard Medical School. [5] [15] She used functional screening of cDNA libraries to define novel regulators of early embryonic development. These included Geminin (Gmnn), a novel nuclear protein that she identified based on its ability to expand the Xenopus neural plate at the expense of non-neural tissue. [5] [16]

Kroll joined the Department of Developmental Biology (previously Dept. of Molecular Biology and Pharmacology) at Washington University School of Medicine in 2000. Her laboratory has focused on identifying how transcriptional and epigenetic regulation controls various aspects of neural development. [2] [3]

Research areas

A major focus of work in the Kroll laboratory has been to identify mechanisms underlying transcriptional and epigenetic control of embryonic development. [17] [18] [19] [20] [21] [22] [23] [24] They demonstrated that Gmnn plays an essential role in these processes, showing that Gmnn is required for neural fate acquisition of embryonic stem cells and promotes an accessible and hyperacetylated chromatin state that facilitates neural gene transcription [19] while also limiting non-neural fate acquisition (endoderm/mesoderm) through functional cooperativity with Polycomb complex (PcG)-mediated epigenetic repression. [18] [20] They demonstrated that Gmnn associates with and promotes histone acetylation at regulatory elements of many neurodevelopmental genes and used these data to construct gene regulatory networks underlying neural fate acquisition. [5] [17] [19]

Beyond early cell fate acquisition, they also defined other aspects of development that require Gmnn, including regulating gene expression during neurogenesis, neuronal differentiation, and neural tube patterning and controlling Hox gene regulation to pattern the vertebrate limb, and they also demonstrated that Gmnn deficiency enhanced survival and response to therapy in mouse models of the pediatric brain tumor medulloblastoma. [25] [26] This body of work established Gmnn as a key cell-intrinsic regulator of several aspects of embryogenesis through its interactions with the SWI/SNF and Polycomb chromatin-modifying complexes. [5] [23] [27] [28] [29] [30]

Current work in the Kroll laboratory uses directed differentiation of human pluripotent stem cells to identify regulatory networks controlling the development of human neuronal cell types that are frequently disrupted in neurodevelopmental disorders. These include cortical interneurons (cINs), GABAergic inhibitory neurons that modulate excitatory neuronal activity in the cortex by providing local inhibition. The laboratory developed modified protocols for directed differentiation of human pluripotent stem cells (hPSCs) efficiently into cINs that provide an effective model for elucidating mechanisms of human cIN development. They have subsequently used this model to define regulatory networks that control human cIN development. [31] [32] [33]

As of 2021, Kroll leads efforts to characterize how pathogenic gene variants contribute to intellectual and developmental disabilities (IDDs) in hPSC-derived models at Washington University School of Medicine (WUSM). She leads the Cellular Models program for WUSM's Intellectual and Developmental Disabilities Research Center (IDDRC), coordinating with the IDDRC's Clinical-Translational Core to build patient-derived cellular models of IDDs.[ citation needed ] She coordinates human cell and organoid-based modeling under WUSM's Precision Medicine Integrated Experimental Resources (PreMIER) platform, WU's model organism screening platform for precision medicine. She also co-leads 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. [34]

Awards

Kroll has received several awards for her work, including the March of Dimes Basil O’Connor Award, the American Cancer Society Research Scholar grant, and American Cancer Society Hope Award. [35] Her other awards include:

Service contributions

Personal life

Kroll is married to John D. Bradley, a scientist at Bayer. [37] [38] Her sister, Jennifer Lee Kroll, died on May 9, 2020, at 52 years of age, due to metastatic breast cancer. She was writer who published more than 30 books. [39] [40] Kroll is also the granddaughter of Josephine LeGrave Wautlet, author of several works, including a language course called Phonetic Walloon for Belgian Americans. [2] [3] Her grandmother was also featured in an oral history on Belgian Americans and the Walloon language (University of Wisconsin, Green Bay). [41]

Selected publications

Kristen Kroll has more than 50 publications in the field of developmental biology including:

Related Research Articles

Developmental biology is the study of the process by which animals and plants grow and develop. Developmental biology also encompasses the biology of regeneration, asexual reproduction, metamorphosis, and the growth and differentiation of stem cells in the adult organism.

<i>Xenopus</i> Genus of amphibians

Xenopus is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-known species of this genus are Xenopus laevis and Xenopus tropicalis, which are commonly studied as model organisms for developmental biology, cell biology, toxicology, neuroscience and for modelling human disease and birth defects.

<span class="mw-page-title-main">Cellular differentiation</span> Developmental biology

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. However, metabolic composition does get altered quite dramatically where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the character Sonic the Hedgehog.

Escargot (esg) is a transcription factor expressed in Drosophila melanogaster. It is responsible for the maintenance of intestinal stem cells and is used as a marker for those types of cells in Drosophila. Apart from its expression in the gut, esg is also expressed in expressed in germline stem cells and cyst stem cells of the testis and, during development, in neural stem cells and imaginal disks.

In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as Drosophila, neuroblasts are neural progenitor cells which divide asymmetrically to produce a neuroblast, and a daughter cell of varying potency depending on the type of neuroblast. Vertebrate neuroblasts differentiate from radial glial cells and are committed to becoming neurons. Neural stem cells, which only divide symmetrically to produce more neural stem cells, transition gradually into radial glial cells. Radial glial cells, also called radial glial progenitor cells, divide asymmetrically to produce a neuroblast and another radial glial cell that will re-enter the cell cycle.

<span class="mw-page-title-main">Neural crest</span> Pluripotent embyronic cell group giving rise to diverse cell lineages

Neural crest cells are a temporary group of cells that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.

<span class="mw-page-title-main">GLI2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor.

<span class="mw-page-title-main">Geminin</span> Nuclear protein inhibiting DNA replication

Geminin, DNA replication inhibitor, also known as GMNN, is a protein in humans encoded by the GMNN gene. A nuclear protein present in most eukaryotes and highly conserved across species, numerous functions have been elucidated for geminin including roles in metazoan cell cycle, cellular proliferation, cell lineage commitment, and neural differentiation. One example of its function is the inhibition of Cdt1.

<span class="mw-page-title-main">HES1</span> Protein-coding gene in the species Homo sapiens

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

<span class="mw-page-title-main">Homeobox protein goosecoid</span> Protein-coding gene in the species Homo sapiens

Homeobox protein goosecoid(GSC) is a homeobox protein that is encoded in humans by the GSC gene. Like other homeobox proteins, goosecoid functions as a transcription factor involved in morphogenesis. In Xenopus, GSC is thought to play a crucial role in the phenomenon of the Spemann-Mangold organizer. Through lineage tracing and timelapse microscopy, the effects of GSC on neighboring cell fates could be observed. In an experiment that injected cells with GSC and observed the effects of uninjected cells, GSC recruited neighboring uninjected cells in the dorsal blastopore lip of the Xenopus gastrula to form a twinned dorsal axis, suggesting that the goosecoid protein plays a role in the regulation and migration of cells during gastrulation.

Maternal to zygotic transition (MZT), also known as embryonic genome activation, is the stage in embryonic development during which development comes under the exclusive control of the zygotic genome rather than the maternal (egg) genome. The egg contains stored maternal genetic material mRNA which controls embryo development until the onset of MZT. After MZT the diploid embryo takes over genetic control. This requires both zygotic genome activation (ZGA), and degradation of maternal products. This process is important because it is the first time that the new embryonic genome is utilized and the paternal and maternal genomes are used in combination. The zygotic genome now drives embryo development.

<span class="mw-page-title-main">FOXA2</span> Mammalian protein found in Homo sapiens

Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer.

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.

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<span class="mw-page-title-main">Dorsal lip</span>

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A developmental signaling center is defined as a group of cells that release various morphogens which can determine the fates, or destined cell types, of adjacent cells. This process in turn determines what tissues the adjacent cells will form. Throughout the years, various development signaling centers have been discovered.

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References

  1. ↑ Kenosha News. Wed. August 31, 1994. Kristen Kroll receives PhD from UC Berkeley.
  2. 1 2 3 4 5 6 "New Models to Understand the Intricacies of Neurodevelopmental Disorders". scientia.global. 2021-04-21. Retrieved 2022-04-25.
  3. 1 2 3 "Using human models of brain development to understand autism". Open Access Government. 2021-08-16. Retrieved 2022-04-25.
  4. ↑ "Jake's mice: Searching for answers to the puzzle of autism". AP NEWS. 2022-01-02. Retrieved 2022-04-25.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "New Models to Understand the Intricacies of Neurodevelopmental Disorders". scientia.global. 2021-04-21. Retrieved 2022-04-25.
  6. ↑ Kenosha News. Friday July 29, 1988. Kristen Kroll receives BA degree from Northwestern University.
  7. ↑ Kenosha News. Thurs. May 24, 1984. Kristen Kroll graduates Wilmot HS.
  8. ↑ Kroll KL, Amaya E (October 1996). "Transgenic Xenopus embryos from sperm nuclear transplantations reveal FGF signaling requirements during gastrulation". Development. 122 (10): 3173–83. doi:10.1242/dev.122.10.3173. PMID   8898230. S2CID   20349983.
  9. ↑ Kroll KL, Gerhart JC (October 1994). "Transgenic X. laevis embryos from eggs transplanted with nuclei of transfected cultured cells". Science. 266 (5185): 650–3. Bibcode:1994Sci...266..650K. doi:10.1126/science.7939720. PMID   7939720.
  10. ↑ Beck CW, Slack JM (2001). "An amphibian with ambition: a new role for Xenopus in the 21st century". Genome Biol. 2 (10): REVIEWS1029. doi: 10.1186/gb-2001-2-10-reviews1029 . PMC   138973 . PMID   11597339.
  11. ↑ Slack JM (October 1996). "Developmental biology. High hops of transgenic frogs". Nature. 383 (6603): 765–6. doi: 10.1038/383765a0 . PMID   8892997.
  12. ↑ Vogel G (July 1999). "Frog is a prince of a new model organism". Science. 285 (5424): 25. doi:10.1126/science.285.5424.25. PMID   10428694. S2CID   24553868.
  13. ↑ Showell C, Conlon FL (June 2007). "Decoding development in Xenopus tropicalis". Genesis. 45 (6): 418–26. doi:10.1002/dvg.20286. PMC   2668205 . PMID   17549727.
  14. ↑ Smith JC (November 1996). "Transgenic frogs and FGF signalling in early development". Trends Genet. 12 (11): 439–40. doi:10.1016/0168-9525(96)30105-4. PMID   8973142.
  15. ↑ Damon Runyon Cancer Research Foundation awardees.
  16. ↑ Kroll KL, Salic AN, Evans LM, Kirschner MW (August 1998). "Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation". Development. 125 (16): 3247–58. doi:10.1242/dev.125.16.3247. PMID   9671596.
  17. 1 2 Sankar S, Yellajoshyula D, Zhang B, Teets B, Rockweiler N, Kroll KL (November 2016). "Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1". Sci Rep. 6: 37412. Bibcode:2016NatSR...637412S. doi:10.1038/srep37412. PMC   5121602 . PMID   27881878.
  18. 1 2 Caronna EA, Patterson ES, Hummert PM, Kroll KL (August 2013). "Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression". Stem Cells. 31 (8): 1477–87. doi:10.1002/stem.1410. PMC   3776023 . PMID   23630199.
  19. 1 2 3 Yellajoshyula D, Patterson ES, Elitt MS, Kroll KL (February 2011). "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. 108 (8): 3294–9. Bibcode:2011PNAS..108.3294Y. doi: 10.1073/pnas.1012053108 . PMC   3044367 . PMID   21300881.
  20. 1 2 Lim JW, Hummert P, Mills JC, Kroll KL (January 2011). "Geminin cooperates with Polycomb to restrain multi-lineage commitment in the early embryo". Development. 138 (1): 33–44. doi:10.1242/dev.059824. PMC   2998164 . PMID   21098561.
  21. ↑ Seo S, Lim JW, Yellajoshyula D, Chang LW, Kroll KL (December 2007). "Neurogenin and NeuroD direct transcriptional targets and their regulatory enhancers". EMBO J. 26 (24): 5093–108. doi:10.1038/sj.emboj.7601923. PMC   2140110 . PMID   18007592.
  22. ↑ Seo S, Richardson GA, Kroll KL (January 2005). "The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD". Development. 132 (1): 105–15. doi:10.1242/dev.01548. PMID   15576411. S2CID   6987785.
  23. 1 2 Seo S, Herr A, Lim JW, Richardson GA, Richardson H, Kroll KL (July 2005). "Geminin regulates neuronal differentiation by antagonizing Brg1 activity". Genes Dev. 19 (14): 1723–34. doi:10.1101/gad.1319105. PMC   1176010 . PMID   16024661.
  24. ↑ Yellajoshyula D, Lim JW, Thompson DM, Witt JS, Patterson ES, Kroll KL (November 2012). "Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis". Mol Cell Biol. 32 (22): 4549–60. doi:10.1128/MCB.00737-12. PMC   3486176 . PMID   22949506.
  25. ↑ Lewis E, Sankar S, Tong C, Patterson ES, Waller LE, Gontarz P, Zhang B, Ornitz DM, Kroll KL (August 2020). "Geminin is required for Hox gene regulation to pattern the developing limb". Dev Biol. 464 (1): 11–23. doi:10.1016/j.ydbio.2020.05.007. PMC   8362291 . PMID   32450229.
  26. ↑ Patterson ES, Waller LE, Kroll KL (September 2014). "Geminin loss causes neural tube defects through disrupted progenitor specification and neuronal differentiation". Dev Biol. 393 (1): 44–56. doi:10.1016/j.ydbio.2014.06.021. PMC   4134736 . PMID   24995796.
  27. ↑ Aigner S, Gage FH (August 2005). "A small gem with great powers: geminin keeps neural progenitors thriving". Dev Cell. 9 (2): 171–2. doi: 10.1016/j.devcel.2005.07.005 . PMID   16054024.
  28. ↑ Kaeser MD, Emerson BM (October 2006). "Remodeling plans for cellular specialization: unique styles for every room". Curr Opin Genet Dev. 16 (5): 508–12. doi:10.1016/j.gde.2006.08.001. PMID   16905306.
  29. ↑ de la Serna IL, Ohkawa Y, Imbalzano AN (June 2006). "Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers". Nat Rev Genet. 7 (6): 461–73. doi:10.1038/nrg1882. PMID   16708073. S2CID   24086145.
  30. ↑ Kondo T (October 2006). "Epigenetic alchemy for cell fate conversion". Curr Opin Genet Dev. 16 (5): 502–7. doi:10.1016/j.gde.2006.07.001. PMID   16844365.
  31. ↑ Meganathan K, Prakasam R, Baldridge D, Gontarz P, Zhang B, Urano F, Bonni A, Maloney SE, Turner TN, Huettner JE, Constantino JN, Kroll KL (July 2021). "Altered neuronal physiology, development, and function associated with a common chromosome 15 duplication involving CHRNA7". BMC Biol. 19 (1): 147. doi: 10.1186/s12915-021-01080-7 . PMC   8317352 . PMID   34320968.
  32. ↑ Lewis E, Meganathan K, Baldridge D, Gontarz P, Zhang B, Bonni A, Constantino JN, Kroll KL (2019). "Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons". Mol Autism. 10: 51. doi: 10.1186/s13229-019-0306-0 . PMC   6936127 . PMID   31893020.
  33. ↑ Meganathan K, Lewis E, Gontarz P, Liu S, Stanley EG, Elefanty AG, Huettner JE, Zhang B, Kroll KL (December 2017). "Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development". Proc Natl Acad Sci U S A. 114 (52): E11180–E11189. Bibcode:2017PNAS..11411180M. doi: 10.1073/pnas.1712365115 . PMC   5748186 . PMID   29229852.
  34. ↑ Anderson NC, Chen PF, Meganathan K, Afshar Saber W, Petersen AJ, Bhattacharyya A, Kroll KL, Sahin M (June 2021). "Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders". Stem Cell Reports. 16 (6): 1446–1457. doi:10.1016/j.stemcr.2021.03.025. PMC   8190574 . PMID   33861989.
  35. ↑ "Kristen L. Kroll - Washington University School of Medicine". Open Access Government. Retrieved 2022-03-24.
  36. ↑ Kenosha News. Monday June 9, 2003. Kristen Kroll inducted into Wilmot HS hall of fame.
  37. ↑ Sunday News-Kenosha News. Sunday July 28, 1991. Kristen Kroll and John Bradley wedding.
  38. ↑ Kenosha News. Saturday March 23, 1991. Kristen Kroll and John Bradley engagement.
  39. ↑ Kenosha News. Sunday May 17, 2020. Jennifer Kroll obituary.
  40. ↑ Jennifer Lee Kroll (1967 - 2020). Legacy.com.
  41. ↑ McAuley, Lynn C. (1976-04-13). "Oral history with Edward and Josephine Wautlet, and Grace and Harvey LeMense, in 6 parts - UWDC". UW-Madison Libraries. Retrieved 2022-04-25.
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