Seung Tae Baek

The Rockefeller University, New York, New York, United States

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Publications (10)96.46 Total impact

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    ABSTRACT: Focal malformations of cortical development (FMCDs) account for the majority of drug-resistant pediatric epilepsy. Postzygotic somatic mutations activating the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway are found in a wide range of brain diseases, including FMCDs. It remains unclear how a mutation in a small fraction of cells disrupts the architecture of the entire hemisphere. Within human FMCD-affected brain, we found that cells showing activation of the PI3K-AKT-mTOR pathway were enriched for the AKT3(E17K) mutation. Introducing the FMCD-causing mutation into mouse brain resulted in electrographic seizures and impaired hemispheric architecture. Mutation-expressing neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration defect in neighboring cells, due at least in part to derepression of reelin transcription in a manner dependent on the forkhead box (FOX) transcription factor FOXG1. Treatments aimed at either blocking downstream AKT signaling or inactivating reelin restored migration. These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inhibitors as potential treatments or therapies for some forms of focal epilepsy.
    Nature medicine 11/2015; DOI:10.1038/nm.3982 · 27.36 Impact Factor
  • Hoon-Chul Kang · Seung Tae Baek · Saera Song · Joseph G Gleeson ·

    The Journal of pediatrics 09/2015; DOI:10.1016/j.jpeds.2015.07.049 · 3.79 Impact Factor
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    ABSTRACT: Somatic and germline duplications or activating mutations of AKT3 have been reported in patients with hemimegalencephaly and megalencephaly. We performed array comparative genomic hybridization on brain tissue and blood in 16 consecutive patients with symptomatic epilepsy due to focal or multilobar malformations of cortical development who underwent surgical treatment of epilepsy. One patient with infantile spasms and a dysplastic left frontal lobe harboured a somatic trisomy of the 1q21.1-q44 chromosomal region, encompassing the AKT3 gene, in the dysplastic brain tissue but not in blood and saliva. Histopathology revealed severe cortical dyslamination, a thin cortex in the premotor area with microgyri and microsulci, immature neurons with disoriented dendrites and areas of cortical heterotopia in the sub-cortical white matter. These cytoarchitectural changes are close to those defining type Ib focal cortical dysplasia. Immunohistochemistry in brain specimens demonstrated hyperactivation of the PI3K/AKT/mTOR pathway. These findings indicate that AKT3 upregulation may cause focal malformations of cortical development. There appears to be an etiologic continuum between hemimegalencephaly and focal cortical dysplastic lesions. The extension of brain malformations due to AKT3 upregulation may be related to the embryonic stage when the postzygotic gene alteration occurs.
    Clinical Genetics 08/2014; 88(3). DOI:10.1111/cge.12476 · 3.93 Impact Factor
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    ABSTRACT: Acute gene inactivation using short hairpin RNA (shRNA, knockdown) in developing brain is a powerful technique to study genetic function; however, discrepancies between knockdown and knockout murine phenotypes have left unanswered questions. For example, doublecortin (Dcx) knockdown but not knockout shows a neocortical neuronal migration phenotype. Here we report that in utero electroporation of shRNA, but not siRNA or miRNA, to Dcx demonstrates a migration phenotype in Dcx knockouts akin to the effect in wild-type mice, suggesting shRNA-mediated off-target toxicity. This effect was not limited to Dcx, as it was observed in Dclk1 knockouts, as well as with a fraction of scrambled shRNAs, suggesting a sequence-dependent but not sequence-specific effect. Profiling RNAs from electroporated cells showed a defect in endogenous let7 miRNA levels, and disruption of let7 or Dicer recapitulated the migration defect. The results suggest that shRNA-mediated knockdown can produce untoward migration effects by altering endogenous miRNA pathways.
    Neuron 06/2014; 82(6):1255-62. DOI:10.1016/j.neuron.2014.04.036 · 15.05 Impact Factor
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    Gaia Novarino · Seung Tae Baek · Joseph G Gleeson ·
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    ABSTRACT: In the September 12, 2013 issue of Nature, the Epi4K Consortium (Allen et al., 2013) reported sequencing 264 patient trios with epileptic encephalopathies. The Consortium focused on genes exceptionally intolerant to sequence variations and found substantial interconnections with autism and intellectual disability gene networks.
    Neuron 10/2013; 80(1):9-11. DOI:10.1016/j.neuron.2013.09.019 · 15.05 Impact Factor
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    ABSTRACT: Combining human genomics and molecular biology, recent studies have made pivotal progress toward understanding the cause of hemimegalencephaly (HME) and other cerebral megalencephaly syndromes. The present article highlights recent advances of the genetic cause of these conditions, and considers the role of somatic postzygotic genetic lesions in brain maldevelopment. Studies over the past 12 months have identified de-novo somatic mutations as one possible cause in HME. The gene mutations involve components of the phosphatidylinositol 3-kinase (PI3K)-AKT (also known as protein kinase B)-mammalian target of rapamycin (mTOR) pathway and include PIK3CA, PIK3R2, AKT3, and MTOR. These mutations were identified by comparing genomic data obtained from surgically resected brain tissue with nondiseased tissue, and by single-neuron sequencing in combination with molecular biology techniques. The association between the somatic mutations and downstream activation of the PI3K-mTOR pathway suggests that HME is a neurodevelopmental disease caused by gain-of-function activation of the PI3K-AKT-mTOR pathway. The studies reviewed suggest that somatic mutations of the PI3K-AKT-mTOR pathway limited to the brain may represent one cause of HME. Dysregulation of this pathway has possible therapeutic potential in the identification of HME. Somatic mutations may be an important yet underappreciated disease mechanism in developmental neurological diseases.
    Current opinion in neurology 04/2013; 26(2):122-7. DOI:10.1097/WCO.0b013e32835ef373 · 5.31 Impact Factor
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    ABSTRACT: The basic helix-loop-helix (bHLH) family of transcription factors orchestrates cell-fate specification, commitment and differentiation in multiple cell lineages during development. Here, we describe the role of a bHLH transcription factor, Tcf21 (epicardin/Pod1/capsulin), in specification of the cardiac fibroblast lineage. In the developing heart, the epicardium constitutes the primary source of progenitor cells that form two cell lineages: coronary vascular smooth muscle cells (cVSMCs) and cardiac fibroblasts. Currently, there is a debate regarding whether the specification of these lineages occurs early in the formation of the epicardium or later after the cells have entered the myocardium. Lineage tracing using a tamoxifen-inducible Cre expressed from the Tcf21 locus demonstrated that the majority of Tcf21-expressing epicardial cells are committed to the cardiac fibroblast lineage prior to initiation of epicardial epithelial-to-mesenchymal transition (EMT). Furthermore, Tcf21 null hearts fail to form cardiac fibroblasts, and lineage tracing of the null cells showed their inability to undergo EMT. This is the first report of a transcription factor essential for the development of cardiac fibroblasts. We demonstrate a unique role for Tcf21 in multipotent epicardial progenitors, prior to the process of EMT that is essential for cardiac fibroblast development.
    Development 05/2012; 139(12):2139-49. DOI:10.1242/dev.079970 · 6.46 Impact Factor
  • Seung Tae Baek · Michelle D Tallquist ·
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    ABSTRACT: The epicardium is the primary source of coronary vascular smooth muscle cells (cVSMCs) and fibroblasts that reside in the compact myocardium. To form these epicardial-derived cells (EPDCs), the epicardium undergoes the process of epithelial to mesenchymal transition (EMT). Although several signaling pathways have been identified that disrupt EMT, no pathway has been reported that restricts this developmental process. Here, we identify neurofibromin 1 (Nf1) as a key mediator of epicardial EMT. To determine the function of Nf1 during epicardial EMT and the formation of epicardial derivatives, cardiac fibroblasts and cVSMCs, we generated mice with a tissue-specific deletion of Nf1 in the epicardium. We found that mutant epicardial cells transitioned more readily to mesenchymal cells in vitro and in vivo. The mesothelial epicardium lost epithelial gene expression and became more invasive. Using lineage tracing of EPDCs, we found that the process of EMT occurred earlier in Nf1 mutant hearts, with an increase in epicardial cells entering the compact myocardium. Moreover, loss of Nf1 caused increased EPDC proliferation and resulted in more cardiac fibroblasts and cVSMCs. Finally, we were able to partially reverse the excessive EMT caused by loss of Nf1 by disrupting Pdgfrα expression in the epicardium. Conversely, Nf1 activation was able to inhibit PDGF-induced epicardial EMT. Our results demonstrate a regulatory role for Nf1 during epicardial EMT and provide insights into the susceptibility of patients with disrupted NF1 signaling to cardiovascular disease.
    Development 04/2012; 139(11):2040-9. DOI:10.1242/dev.074054 · 6.46 Impact Factor
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    ABSTRACT: Tcf21 is a Class II bHLH family member with essential roles in the formation of the lungs, kidneys, gonads, spleen, and heart. Here, we report the utility of a mouse line with targeted insertion of a tamoxifen-inducible Cre recombinase, MerCreMer at the Tcf21 locus. This mouse line will permit the inducible expression of Cre recombinase in Tcf21-expressing cells. Using ROSA26 reporter mice, we show that Cre recombinase is specifically and robustly activated in multiple Tcf21-expressing tissues during embryonic and postnatal development. The expression profile in the kidney is particularly dynamic with the ability to cause recombination in mesangial cells at one time of induction and podocytes at another time. These features make the Tcf21-driven inducible Cre line (Tcf21(iCre) ) a valuable genetic tool for spatiotemporal gene function analysis and lineage tracing of cells in the heart, kidney, cranial muscle, and gonads.
    genesis 11/2011; 49(11):870-7. DOI:10.1002/dvg.20750 · 2.02 Impact Factor
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    ABSTRACT: In early heart development, platelet-derived growth factor (PDGF) receptor expression in the heart ventricles is restricted to the epicardium. Previously, we showed that PDGFRβ is required for coronary vascular smooth muscle cell (cVSMC) development, but a role for PDGFRα has not been identified. Therefore, we investigated the combined and independent roles of these receptors in epicardial development. To understand the contribution of PDGF receptors in epicardial development and epicardial-derived cell fate determination. By generating mice with epicardial-specific deletion of the PDGF receptors, we found that epicardial epithelial-to-mesenchymal transition (EMT) was defective. Sox9, an SRY-related transcription factor, was reduced in PDGF receptor-deficient epicardial cells, and overexpression of Sox9 restored epicardial migration, actin reorganization, and EMT gene expression profiles. The failure of epicardial EMT resulted in hearts that lacked epicardial-derived cardiac fibroblasts and cVSMC. Loss of PDGFRα resulted in a specific disruption of cardiac fibroblast development, whereas cVSMC development was unperturbed. Signaling through both PDGF receptors is necessary for epicardial EMT and formation of epicardial-mesenchymal derivatives. PDGF receptors also have independent functions in the development of specific epicardial-derived cell fates.
    Circulation Research 06/2011; 108(12):e15-26. DOI:10.1161/CIRCRESAHA.110.235531 · 11.02 Impact Factor

Publication Stats

201 Citations
96.46 Total Impact Points


  • 2015
    • The Rockefeller University
      New York, New York, United States
  • 2014
    • University of California, San Diego
      San Diego, California, United States
  • 2013-2014
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2011-2012
    • University of Texas Southwestern Medical Center
      • Department of Molecular Biology
      Dallas, Texas, United States