Jan Krzysztof Blusztajn, Ph.D.

Professor

Contact Information

Email: jbluszta@bu.edu
Tel. 617-638-4829

Education

M.S. Molecular Biology; Warsaw University
Ph.D. Neural and Endocrine Regulation; Massachusetts Institute of Technology

Research Interests

Prenatal programming of brain development and aging by essential nutrient availability during gestation

We study the effects of perinatal availability of an essential nutrient, choline, on brain development and aging in experimental animals. This research endeavors to determine why it is that supplementation with choline during critical perinatal periods in rats and mice causes a long-term facilitation of visuospatial memory which persists until old age. To this end we are utilizing biochemical, neuroanatomical, and behavioral techniques in a highly unified experimental design. Our studies to date have focused on the development of the basal forebrain cholinergic system, hippocampal MAPK and CREB signaling, and on the developmental patterns of brain gene expression ( Fig. 1). Recent data prompted us to test the hypothesis that the actions of choline are mediated by an epigenetic mechanism involving DNA methylation. Because choline is a donor of metabolic methyl groups its levels modulate the concentrations of cellular S?adenosylmethionine, a compound that serves as a substrate for DNA methylating enzymes. In turn, DNA methylation patterns modulate transcription of multiple genes. These methylation patterns are inherited through cell divisions, providing a possible epigenetic mechanism for modifications in brain gene expression observed many months after the dietary manipulation. Indeed, we found that prenatal availability of choline alters global DNA methylation and patterns of DNA methylation of key genes (e.g. insulin-like growth factor II, Igf2) whose expression is known to be regulated by this process. Our data are the first to indicate that choline nutrition in pregnancy alters the epigenome of the brain. Perhaps surprisingly, we observed upregulation of DNA methylation during choline deficiency. We hypothesized that this may be due to induced expression of DNA methylating enzymes by low choline supply. Indeed, choline deficiency increased the expression of DNA methyltransferases, DNMT1 and DNMT3A in brain and liver. These data point to an apparently adaptive epigenomic response to varied gestational choline supply in rat fetal liver and brain. We are vigorously pursuing the testing of the methylation hypothesis [both as it relates to DNA and histones] and we are producing genetic mouse models that help us understand the mechanism of action of choline.

PKCb2, GABABR1, and CAMKIIb. See Mellott et al, 2007. Fig. 1. Hierarchal clustering of hippocampal mRNA expression microarray data from prenatally choline-supplemented (S), control (C) and choline-deficient (D) rats on postnatal day 18. Arrays and genes were clustered according to the similarity of their expression level to their adjacent neighbor. Red represents high expression and green low expression, relative to mean (black). The results show that the three dietary groups are differentiated from each other. This illustration shows the 303 genes in nine arrays from P18 animals and a magnification of the three genes that were analyzed in subsequent studies: PKC?2, GABABR1, and CAMKII?. See Mellott et al, 2007

Induction and maintenance of neuronal neurotransmitter phenotype: focus on basal forebrain cholinergic neurons

Our second interest is the regulation of the expression of the cholinergic phenotype, i.e. of the genes coding for proteins involved in the synthesis (choline acetyltransferase and choline transporter) and the storage (the vesicular acetylcholine transporter) of the neurotransmitter, acetylcholine (ACh) (Fig. 2). Those studies include molecular biological characterization of the promoter regions of these genes, as well as studies aimed at examining the regulation of their expression during brain development and aging. Our current research focuses on the molecular mechanisms whereby bone morphogenetic protein 9 (BMP9) induce the cholinergic phenotype in neuronal precursor cells. We focus on the basal forebrain cholinergic neurons (BFCN). These cells are important for such functions as learning, memory and attention. We found that BMP9 is expressed in the developing basal forebrain, making it a candidate for an endogenous differentiating factor for BFCN, and possibly also for a maintenance trophic factor for these cells in adulthood. These possibilities are being tested using purified BFCN, isolated by fluorescence-activated cell sorting. The key question that we wish to answer is what are the signaling pathways and transcription factors that allow BFCN to express their cholinergic phenotype.

Fig. 2. Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) that transfers the acetate moiety from acetyl-CoA onto choline. The newly-formed ACh is transported into synaptic vesicles by vesicular ACh transporter (VAChT). Neuronal activity causes exocytosis of ACh into the synaptic cleft where it can interact with postsynaptic receptors to propagate the signal. The muscarinic receptors (mAChR) are G-protein-coupled seven transmembrane domain proteins whereas the nicotinic receptors (nAChR) are ligand-gated ion channels. In order to terminate the action of ACh, intrasynaptic acetylcholinesterase (AChE) hydrolyses it into acetate and choline. Most of the latter is taken up into the presynaptic neuron by choline transporter Cht1 and it is thus recycled for an additional round of ACh synthesis. Illustration and animation by J.K. Blusztajn and P. Kaczmarek

See Selected Recent Publications below or Search Additional Publications in PubMed

  • Blusztajn, J. K., and Berse, B. (2000) The cholinergic neuronal phenotype in Alzheimer’s disease. Metab Brain Dis 15, 45-64 PubMed
  • Farber, S. A., Slack, B. E., and Blusztajn, J. K. (2000) Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer’s disease. FASEB J 14, 2198-2206 PubMed
  • Lopez-Coviella, I., Berse, B., Krauss, R., Thies, R. S., and Blusztajn, J. K. (2000) Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science 289, 313-316 PubMed
  • Yang, Y., Liu, Z., Cermak, J. M., Tandon, P., Sarkisian, M. R., Stafstrom, C. E., Neill, J. C., Blusztajn, J. K., and Holmes, G. L. (2000) Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J Neurosci 20, RC109 PubMed
  • Guo-Ross, S. X., Clark, S., Montoya, D. A., Jones, K. H., Obernier, J., Shetty, A. K.,
    White, A. M., Blusztajn, J. K., Wilson, W. A., and Swartzwelder, H. S. (2002)
    Prenatal choline supplementation protects against postnatal neurotoxicity. J Neurosci 22, RC195
    PubMed
  • Holmes, G. L., Yang, Y., Liu, Z., Cermak, J. M., Sarkisian, M. R., Stafstrom, C. E., Neill, J. C., and Blusztajn, J. K. (2002) Seizure-induced memory impairment is reduced by choline supplementation before or after status epilepticus. Epilepsy Res 48, 3-13 PubMed
  • Mellott, T., Lopez-Coviella, I., Blusztajn, J. K., and Berse, B. (2002) Mitogen-activated protein kinase kinase negatively modulates ciliary neurotrophic factor-activated choline acetyltransferase gene expression. Eur J Biochem 269, 850-858 PubMed
  • Brandon, E. P., Mellott, T., Pizzo, D. P., Coufal, N., D’Amour, K. A., Gobeske, K., Lortie, M., Lopez-Coviella, I., Berse, B., Thal, L. J., Gage, F. H., and Blusztajn, J. K. (2004) Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency. J Neurosci 24, 5459-5466 PubMed
  • Mellott, T. J., Williams, C. L., Meck, W. H., and Blusztajn, J. K. (2004) Prenatal  choline supplementation advances hippocampal development and enhances MAPK and CREB activation. Faseb J 18, 545-547 PubMed
  • Lopez-Coviella, I., Follettie, M. T., Mellott, T. J., Kovacheva, V. P., Slack, B. E., Diesl, V., Berse, B., Thies, R. S., and Blusztajn, J. K. (2005) Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons. Proc Natl Acad Sci U S A 102, 6984-6989 PubMed
  • Slack, B. E., Siniaia, M. S., and Blusztajn, J. K. (2006) Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: involvement of Src tyrosine kinase. J Cell Biochem 98, 672-684 PubMed
  • Glenn, M. J., Gibson, E. M., Kirby, E. D., Mellott, T. J., Blusztajn, J. K., and Williams, C. L. (2007) Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats. Eur J Neurosci 25, 2473-2482 PubMed
  • Kovacheva, V. P., Mellott, T. J., Davison, J. M., Wagner, N., Lopez-Coviella, I., Schnitzler, A. C., and Blusztajn, J. K. (2007) Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 282, 31777-31788 PubMed
  • Mellott, T. J., Follettie, M. T., Diesl, V., Hill, A. A., Lopez-Coviella, I., and Blusztajn, J. K. (2007) Prenatal choline availability modulates hippocampal and cerebral cortical gene expression. FASEB J 21, 1311-1323 PubMed
  • Meck, W. H., Williams, C. L., Cermak, J. M., and Blusztajn, J. K. (2007) Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integr Neurosci 1, 7 PubMed
  • Schnitzler,A. C., Lopez-Coviella, I., and Blusztajn, J. K. (2008) Purification and culture of nerve growth factor receptor (p75)-expressing basal forebrain cholinergic neurons. Nat Protoc 3, 34-40 PubMed
  • Slack, B. E., and Blusztajn, J. K. (2008) Differential regulation of mTOR-dependent S6 phosphorylation by muscarinic acetylcholine receptor subtypes. J Cell Biochem 104, 1818-1831 PubMed
  • Wong-Goodrich, S. J., Mellott, T. J., Glenn, M. J., Blusztajn, J. K., and Williams, C. L. (2008) Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus. Neurobiol Dis 30, 255-269 PubMed
  • Glenn, M.J., Gibson, E.M., Kirby, E.D., Wong-Goodrich, S.J.E., Mellott, T.J., Blusztajn, J.K. and Williams, C.L. (2008) Age-related declines in exploratory behavior and markers of hippocampal plasticity are attenuated by prenatal choline supplementation in rats. Brain Res 1237, 110-123 PubMed
  • Schnitzler, A.C., Lopez-Coviella, I. and Blusztajn, J.K. (2008) Differential modulation of nerve growth factor receptor (p75) and cholinergic gene expression in purified p75-expressing and non-expressing basal forebrain neurons by BMP9. Brain Res 1246, 19-28 PubMed
  • Kovacheva, V.P., Davison, J.M., Mellott, T.J., Rogers, A.E., Yang, S., O’Brien M.J. and Blusztajn, J.K. (2009) Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival. FASEB J 23, 1054-1063 PubMed
  • Davison, J.M., Mellott, T.J., Kovacheva, V.P. and Blusztajn, J.K. (2009) Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a) and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem 284, 1982-1989 PubMed
  • Johnson, A.R., Craciunescu, C.N., Guo, Z., Thresher, R.J., Blusztajn, J.K., and Zeisel, SH (2010) Deletion of murine choline dehydrogenase results in diminished sperm motility. FASEB J 24, 2752-2761 PubMed
  • Schnitzler, A.C., Lopez-Coviella, I., Mellott, T.J., Tallini, Y.N., Kotlikoff, M.I., Follettie, M.T. and Blusztajn, J.K. (2010) BMP9 induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons. J Neurosci 30, 8221-8228 PubMed
  • Wong-Goodrich, S.J.E, Mellott, T.J., Liu, B., Blusztajn, J.K. and Williams, C.L. (2011) Water maze experience and prenatal choline supplementation differentially promote long-term hippocampal recovery from seizures in adulthood. Hippocampus 21, 584-608 PubMed
  • Carey, R.M., Blusztajn, J.K. and Slack, B.E. (2011) Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. BMC Cell Biol 12, 20 PubMed

· Blusztajn, J. K., and Berse, B. (2000) The cholinergic neuronal phenotype in Alzheimer’s disease. Metab Brain Dis 15, 45-64 PubMed

· Farber, S. A., Slack, B. E., and Blusztajn, J. K. (2000) Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer’s disease. FASEB J 14, 2198-2206 PubMed

· Lopez-Coviella, I., Berse, B., Krauss, R., Thies, R. S., and Blusztajn, J. K. (2000) Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science 289, 313-316 PubMed

· Yang, Y., Liu, Z., Cermak, J. M., Tandon, P., Sarkisian, M. R., Stafstrom, C. E., Neill, J. C., Blusztajn, J. K., and Holmes, G. L. (2000) Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J Neurosci 20, RC109 PubMed

· Guo-Ross, S. X., Clark, S., Montoya, D. A., Jones, K. H., Obernier, J., Shetty, A. K., White, A. M., Blusztajn, J. K., Wilson, W. A., and Swartzwelder, H. S. (2002) Prenatal choline supplementation protects against postnatal neurotoxicity. J Neurosci 22, RC195 PubMed

· Holmes, G. L., Yang, Y., Liu, Z., Cermak, J. M., Sarkisian, M. R., Stafstrom, C. E., Neill, J. C., and Blusztajn, J. K. (2002) Seizure-induced memory impairment is reduced by choline supplementation before or after status epilepticus. Epilepsy Res 48, 3-13 PubMed

· Mellott, T., Lopez-Coviella, I., Blusztajn, J. K., and Berse, B. (2002) Mitogen-activated protein kinase kinase negatively modulates ciliary neurotrophic factor-activated choline acetyltransferase gene expression. Eur J Biochem 269, 850-858 PubMed

· Brandon, E. P., Mellott, T., Pizzo, D. P., Coufal, N., D’Amour, K. A., Gobeske, K., Lortie, M., Lopez-Coviella, I., Berse, B., Thal, L. J., Gage, F. H., and Blusztajn, J. K. (2004) Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency. J Neurosci 24, 5459-5466 PubMed

· Mellott, T. J., Williams, C. L., Meck, W. H., and Blusztajn, J. K. (2004) Prenatal choline supplementation advances hippocampal development and enhances MAPK and CREB activation. Faseb J 18, 545-547 PubMed

· Lopez-Coviella, I., Follettie, M. T., Mellott, T. J., Kovacheva, V. P., Slack, B. E., Diesl, V., Berse, B., Thies, R. S., and Blusztajn, J. K. (2005) Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons. Proc Natl Acad Sci U S A 102, 6984-6989 PubMed

· Slack, B. E., Siniaia, M. S., and Blusztajn, J. K. (2006) Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: involvement of Src tyrosine kinase. J Cell Biochem 98, 672-684 PubMed

· Glenn, M. J., Gibson, E. M., Kirby, E. D., Mellott, T. J., Blusztajn, J. K., and Williams, C. L. (2007) Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats. Eur J Neurosci 25, 2473-2482 PubMed

· Kovacheva, V. P., Mellott, T. J., Davison, J. M., Wagner, N., Lopez-Coviella, I., Schnitzler, A. C., and Blusztajn, J. K. (2007) Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 282, 31777-31788 PubMed

· Mellott, T. J., Follettie, M. T., Diesl, V., Hill, A. A., Lopez-Coviella, I., and Blusztajn, J. K. (2007) Prenatal choline availability modulates hippocampal and cerebral cortical gene expression. FASEB J 21, 1311-1323 PubMed

· Mellott, T. J., Kowall, N. W., Lopez-Coviella, I., and Blusztajn, J. K. (2007) Prenatal choline deficiency increases choline transporter expression in the septum and hippocampus during postnatal development and in adulthood in rats. Brain Res 1151, 1-11 PubMed

· Meck, W. H., Williams, C. L., Cermak, J. M., and Blusztajn, J. K. (2007) Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integr Neurosci 1, 7 PubMed

· Schnitzler, A. C., Lopez-Coviella, I., and Blusztajn, J. K. (2008) Purification and culture of nerve growth factor receptor (p75)-expressing basal forebrain cholinergic neurons. Nat Protoc 3, 34-40 PubMed

· Slack, B. E., and Blusztajn, J. K. (2008) Differential regulation of mTOR-dependent S6 phosphorylation by muscarinic acetylcholine receptor subtypes. J Cell Biochem 104, 1818-1831 PubMed

· Wong-Goodrich, S. J., Mellott, T. J., Glenn, M. J., Blusztajn, J. K., and Williams, C. L. (2008) Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus. Neurobiol Dis 30, 255-269 PubMed

· Glenn, M.J., Gibson, E.M., Kirby, E.D., Wong-Goodrich, S.J.E., Mellott, T.J., Blusztajn, J.K. and Williams, C.L. (2008) Age-related declines in exploratory behavior and markers of hippocampal plasticity are attenuated by prenatal choline supplementation in rats. Brain Res 1237, 110-123 PubMed

· Schnitzler, A.C., Lopez-Coviella, I. and Blusztajn, J.K. (2008) Differential modulation of nerve growth factor receptor (p75) and cholinergic gene expression in purified p75-expressing and non-expressing basal forebrain neurons by BMP9. Brain Res 1246, 19-28 PubMed

· Kovacheva, V.P., Davison, J.M., Mellott, T.J., Rogers, A.E., Yang, S., O’Brien M.J. and Blusztajn, J.K. (2009) Raising gestational choline intake alters gene expression in DMBA-evoked mammary tumors and prolongs survival. FASEB J 23, 1054-1063 PubMed

· Davison, J.M., Mellott, T.J., Kovacheva, V.P. and Blusztajn, J.K. (2009) Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a) and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem 284, 1982-1989 PubMed

· Johnson, A.R., Craciunescu, C.N., Guo, Z., Thresher, R.J., Blusztajn, J.K., and Zeisel, SH (2010) Deletion of murine choline dehydrogenase results in diminished sperm motility. FASEB J 24, 2752-2761 PubMed

· Schnitzler, A.C., Lopez-Coviella, I., Mellott, T.J., Tallini, Y.N., Kotlikoff, M.I., Follettie, M.T. and Blusztajn, J.K. (2010) BMP9 induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons. J Neurosci 30, 8221-8228 PubMed

· Wong-Goodrich, S.J.E, Mellott, T.J., Liu, B., Blusztajn, J.K. and Williams, C.L. (2011) Water maze experience and prenatal choline supplementation differentially promote long-term hippocampal recovery from seizures in adulthood. Hippocampus 21, 584-608 PubMed

· Carey, R.M., Blusztajn, J.K. and Slack, B.E. (2011) Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. BMC Cell Biol 12, 20 PubMed