Dr. Brad Merrill
- Doctoral Training, Ph.D Biological Sciences, 1999 University of California,San Diego (Advisor:Dr. Connie Holm)
- Postdoctoral Training,1999-2004 University of Chicago and The Rockefeller University, New York (Advisor:Dr. Elaine Fuchs)
Each of the trillions of cells in your body is derived from a single stem cell, the fertilized egg. By dynamically responding to their cellular surroundings, the progeny of this stem cell follow the blueprint encoded by the genome to construct the basic structure of the body, to form tissues and organs, and to maintain physiological systems throughout your lifetime.
In the Merrill lab, we endeavor to reveal fundamental molecular mechanisms driving cell fates decisions, and how these decisions direct embryogenesis and stem cell maintenance in vivo. We center our efforts on the roles of a family of DNA-binding transcriptional regulators called Tcf/Lef factors. Tcf/Lef proteins can either activate or repress transcription of target genes depending upon the cohort of physically interacting proteins available to interact with a Tcf/Lef protein within a given cell (see figure below).
By examining Tcf/Lef knockout and tissue-specific knockout mice, we have identified physiological processes controlled by Tcf/Lef factors. Furthermore, by utilizing in vitro stem cell systems and knockin mutations affecting specific protein-protein interactions, we have begun to unravel the molecular mechanisms that drive these interesting and important cell fate decisions in vivo.
Currently Highlighted Research Directions:
Mechanisms of Tcf3-mediated cell fate decisions during embryogenesis
The early mouse embryo exhibits radial symmetry until approximately embryonic day 6.5, when a cell fate change in a group of cells defines the future posterior and thus the anteroposterior axis of the body. Previously, WNTs have been shown to induce this body axis, yet a requirement for a Tcf/Lef protein had not been discovered until we knocked out the Tcf3 gene. Tcf3-/- mutants form striking duplications of the body axissuch as the tail-head-tail duplications shown here. Further analysis of the defects in Tcf3-/- embryos will elucidate how multiple signaling pathways combine to induce an embryonic axis..
Creating a Tcf3 knockin mutant (DeltaNTcf3), incapable of binding beta-catenin, formally tests whether Tcf3-mediated activation or repression of target genes is required during embryogenesis. Since Tcf3deltaN/deltaN knockin mutants embryos develop with a normal body axis, beta-catenin binding must not be required for Tcf3 function during early embryonic stages, and Tcf3 must repress target genes to prevent axis duplication. Interestingly, Tcf3deltaN/deltaN mice die soon after birth and exhibit craniofacial structural defects. Analysis of the morphogenetic defects in the Tcf3deltaN/deltaN mouse is currently underway and has potential to definitively identify the first physiological requirements for Tcf3-?-catenin interaction in any organism
Roles of Tcf/Lef factors in regulating stem cell fates:
Recently, scientists and the general public alike have realized the importance of understanding basic principles of stem cell biology and the mechanisms by which stem cells self renew. Tcf3 is expressed in multiple stem cell types (hematopoietic, neural, embryonic, hair follicle). In addition, WNT stimulation of hematopoietic stem cells directly activates their self renewal. Interestingly, we have found that compared to Tcf3+/- controls, Tcf3-/- embryonic stem (ES) cells fail to differentiate, suggesting that Tcf3 regulates stem cell self renewal. Identifying the molecular mechanisms and the direct target genes of Tcf3 that control ES cell fates are crucial for understanding the basic biology of stem cells. These insights combined with the ability to remove Tcf3 and beta-catenin from mouse stem cells in vivo with “conditional” knockout alleles, together provide a powerful approach for understanding how stem cells are regulated in their native environment.
Hoffman JA, Wu CI, Merrill BJ. Tcf7l1 prepares epiblast cells in the gastrulating mouse embryo for lineage specification. Development. 2013 Apr;140(8):1665-75. doi: 10.1242/dev.087387. Epub 2013 Mar 13. PubMed PMID: 23487311.
Wu CI, Hoffman JA, Shy BR, Ford EM, Fuchs E, Nguyen H, Merrill BJ. Function of Wnt/β-catenin in counteracting Tcf3 repression through the Tcf3-β-catenin interaction. Development. 2012 Jun;139(12):2118-29. doi: 10.1242/dev.076067. Epub 2012 May 9. PubMed PMID: 22573616; PubMed Central PMCID: PMC3357906.
Yi F, Pereira L, Hoffman JA, Shy BR, Yuen CM, Liu DR, Merrill BJ. Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol. 2011 Jun 19;13(7):762-70. doi: 10.1038/ncb2283. PubMed PMID: 21685894; PubMed Central PMCID: PMC3129424.
Pereira L, Yi F, Merrill BJ. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal. Mol Cell Biol. 2006 Oct;26(20):7479-91. Epub 2006 Aug 7. PubMed PMID: 16894029; PubMed Central PMCID: PMC1636872.