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Bio

Emanuel DiCicco-Bloom is a professor at the Department of Neuroscience and Cell Biology. His research interests include gene and growth factor regulation of neurogenesis during mammalian brain development, focusing on models of human neurodevelopmental disorders, including autism, schizophrenia, and environmental teratogens.

Education

  • MD, Cornell University Medical College, 1977

Research Interests: My main area of research is nervous system development and how abnormalities contribute to brain disease. As a physician-scientist, I am motivated to share knowledge of brain development and scientific discovery with the public, advising advocacy organizations and government agencies on how basic research can help address neurodevelopmental disorders. Building on our pioneering studies of neurogenesis, we defined how extracellular signals, receptors, and genes regulate signaling pathways that control proliferation to produce neurons in diverse brain regions including the cerebellum, cerebral cortex, and hippocampus. Importantly, mechanisms that stimulate or inhibit neurogenesis in culture models reliably translate into living animals.

We have worked in a variety of systems:

1) Since cerebellar abnormalities are repeatedly observed in autism neuropathology, a previous focus was on developmental roles of hindbrain patterning gene, Engrailed-2, a common risk variant. We found that gene deletion had effects not only on cerebellum and hindbrain where monoamine neurons reside, but also secondary effects on monoaminergic target forebrain regions. This model indicates that developmental regulatory genes that may contribute to ASD risk likely have both cell autonomous and non-cell autonomous effects that impact neural connectivity, an autism dysfunction well-documented on human neuroimaging. Current studies are examining how stressful experiences interact with genetic vulnerabilities.

2) Another major focus has been the cerebral cortex, which mediates sophisticated cognitive and social abilities. While different regions serve distinct functions, they all exhibit the common six-layer cytoarchitecture, with deeper layer neurogenesis preceding upper layers. We sought to understand several issues: What signals determine when precursors stop dividing? How do they work? And are these pathways related to disease? We found that positive and negative signals interact to regulate neurogenesis. Specifically, growth factors stimulate (IGF1, bFGF) or inhibit (PACAP) proliferation, though their activity may be stage-specific, depending on receptor isoforms. Further, proliferative signals modulate both arms of the cell cycle machinery, including pro-mitogenic cyclins and CDK inhibitors (p57Kip2, p27Kip1), and influence the timing, numbers, and types of neurons generated. These studies bear relevance to diseases including macrocephaly and autism, depression, and Beckwith-Wiedemann syndrome.

3) Developmental neurogenesis is a target of environmental toxins, like methylmercury. Families in clinic raise concerns about their children’s learning difficulties and wonder about pollutants. The hippocampus is critical for learning and memory, which involves hippocampal neurogenesis. Daily experiences like diet, stress, and drugs influence neuron generation and survival. We find that low levels of methylmercury selectively kill hippocampal stem cells through mitochondrial-dependent apoptosis and produce adolescent deficits in learning and memory. Furthermore, stem cell vulnerability extends to adulthood and includes other compounds, like pesticides (dioxin; deltamethrin). These studies support restrictions on fish consumption during pregnancy and regulation of environmental exposure to pesticides.

More recently, we recognized a gap in our understanding of how genetic and environmental factors that contribute to autism act on the developing fetus. While mouse models implicate effects on behavior, and brain structures, circuits, and synapses, murine cerebral cortex is generated in only 6 days, whereas the human cortex takes 6 months! Thus, we now focus attention on human Neural Precursor Cells generated from individuals with idiopathic and genetically-defined autism, which maintain their person-specific genetic signatures and are revealing common neurobiological phenotypes.

National Advisory Positions: Dr. DiCicco-Bloom serves on several autism and brain disease related scientific panels including the Eagles Autism Challenge, the Autism Science Foundation, and the American Brain Coalition; is Chair of the NIH Developmental Brain Disorders study section; and is a member of the Society for Neuroscience Audit Committee as well as editorial boards of several neuroscience and autism journals.

Selected Publications

  • Nicot, A., Lelièvre, V., Tam, J., Waschek, J.A. and DiCicco-Bloom, E. (2002) Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sonic Hedgehog (Shh) Interact to Control Cerebellar Granule Precursor Cell Proliferation. J Neurosci 22:9244-54.
  • Benayed, R., Gharani, N., Rossman, I., Mancuso, V., Lazar, G., Kamdar, S., Bruse, SE., Tischfield, S., Smith, BJ., Zimmerman, RA., DiCicco-Bloom, E., Brzustowicz, LM., and Millonig, JH. (2005) Support for the homeobox transcription factor, ENGRAILED 2, as an Autism Spectrum Disorder (ASD) susceptibility locus. Am J Hum Genet 77:851-68. Epub 2005 Oct 5.
  • DiCicco-Bloom, E. (2006) Perspectives NEUROSCIENCE: Neuron, Know Thy Neighbor. Science 311:1560-1562. 10.1126/science.1126397
  • DiCicco-Bloom, E., Lord, C., Zwaigenbaum, L., Courchesne, E., Dager, SR., Schmitz, C., Schultz, RT., Crawley, J., and Young, LJ. (2006) The Developmental Neurobiology of Autism Spectrum Disorder. Mini-Review. J Neurosci. 26:6897-6906.
  • DiCicco-Bloom E., It’s a Question of Development: Autism from Bench to Clinic, Neuron (2007), doi:10.1016/j.neuron.2007.03.023
  • Falluel-Morel, A., Sokolowski, K., Sisti, H.M., Zhou, X., Shors, T.J., DiCicco-Bloom, E. (2007) Developmental mercury exposure elicits acute hippocampal cell death, reductions in neurogenesis, and severe learning deficits during puberty. J Neurochem. 2007 Dec; 103(5):1968-81. Epub Aug 30.
  • Falluel-Morel, A., Tascau, L.I., Sokolowski, K., Brabet, P., DiCicco-Bloom, E. (2008) Granule cell survival is deficient in PAC1-/- Mutant cerebellum. J Mol Neurosci. 36(1-3):38-44. 2008 Epub Apr 12.
  • Ye, W., Mairet-Coello, G., Pasoreck, E., DiCicco-Bloom, E. (2008) Patterns of p57Kip2 expression in embryonic rat brain suggest roles in progenitor cell cycle exit and neuronal differentiation. Dev Neurobiol. 2009 Jan; 69(1):1-21, Epub 2008 Sep 23.
  • Mairet-Coello, G., Tury, A., DiCicco-Bloom, E. (2009) IGF-1 promotes G1/S cell cycle progression through bidirectional regulation of cyclins and CDK inhibitors via the PI3K/Akt pathway in developing rat cerebral cortex. J Neurosci. 2009 Jan 21; 29(3):775-88.
  • Tury, A., Mairet-Coello, G., DiCicco-Bloom, E. (2011) The cyclin-dependent kinase inhibitor p57Kip2 regulates cell cycle exit, differentiation, and migration of embryonic cerebral cortical precursors. Cereb Cortex. 2011 Aug;21(8):1840-56. Epub 2011 Jan 18.
  • Sokolowski, K., Falluel-Morel, A., Zhou, X., DiCicco-Bloom, E. (2011) Methylmercury (MeHg) elicits mitochondrial-dependent apoptosis in developing hippocampus and acts at low exposures. Neurotoxicology. 2011 Oct;32(5):535-44. Epub 2011 Jun 29.
  • Tury, A., Mairet-Coello, G., DiCicco-Bloom, E. (2011) The multiple roles of the cyclindependent kinase inhibitory protein p57(KIP2) in cerebral cortical neurogenesis. Dev Neurobiol. 2011 Nov 10. doi: 10.1002/dneu.20999. [Epub ahead of print]
  • Mairet-Coello, G., Tury, A., Van Buskirk, E., Robinson, K., Genestine, M., DiCicco-Bloom, E. (2012) p57(KIP2) regulates radial glia and intermediate precursor cell cycle dynamics and lower layer neurogenesis in developing cerebral cortex. Development; 139(3):475-87.
  • Sokolowski K, Obiorah M, Robinson K, McCandlish E, Buckley B, DiCicco-Bloom E (2013) Neural stem cell apoptosis after low-methylmercury exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits. Dev Neurobiol, 2013 Dec; 73(12):936-49.
  • Rossman IT, Lin L, Morgan KM, Digiovine M, Van Buskirk EK, Kamdar S, Millonig JH, DiCicco-Bloom E. Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development. Mol Autism. 2014 Feb 7; 5(1):9.
  • Hossain MM, DiCicco-Bloom E., Richardson JR (2014) Hippocampal ER stress and learning and memory deficits following repeated pyrethroid exposure. Toxicol Sci 2014 Oct 29. Pii: kfu226
  • Brielmaier J; Senerth JM; Silverman JL; Matteson PG; Millonig JH; DiCicco-Bloom E.; Crawley JN; Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice; Genes, Brain and Behavior, 2014 13:286- 298. doi:10.111/gbb.12115, 2014
  • Tsiperson V, Huang Y, Bagayogo I, Song Y, VonDron MW, DiCicco-Bloom E, Dreyfus CF (2015) Brainderived neurotrophic factormdeficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induceddemyelination. ASN Neuro. 2015 Jan 13;7(1). pii: 1759091414566878. doi:10.1177/1759091414566878. Print 2015 Jan-Feb.
  • Obiorah M, McCandlish E, Buckely B, DiCicco-Bloom E. (2015) Hippocampal developmental vulnerability to methylmercury extends into prepubescence. Front neurosci 2015 May 12;9:150 doi: 10.33389/fnins
  • Genestine M, Lin L, Durens M, Yan Y, Jiang Y, Prem S, Bailoor K, Kelly B, Sonsalla PK, Matteson PG, Silverman J, Crawley JN, Millonig JH, DiCicco-Bloom E. (2015) Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior. Hum Mol Genet 2015 Jul 28. pii ddv301 [Epub ahead of print]
  • Dever DP, Adham ZO, Thompson B, Genestine M, Cherry J, Olschowka JA, DiCiccoBloom E, Opanashuk LA. (2015) Aryl hydrocarbon receptor deletion in cerebellar granule neuron precursors impairs neurogenesis. Dev Neurobiol. 2015 Aug 3. doi:10.1002/dneu.22330. [Epub ahead of print] PMID: 26243376
  • Lee HJ, Dreyfus C, DiCicco-Bloom E (2015) Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat. Dev Neurobiol 2015 Oct 27. Doi: 10.1002.dneu.22359 [Epub before print]
  • Verpeut JL, DiCicco-Bloom E, Bello NT. (2016) Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural actoivation in adult Engrailed 2 null mice. Physiol Behav. 2016 Jul 1;161:90-8. doi:10.1016/j.physbeh.2016.04.001. Epub 2016 Apr 11.
  • Gu N, Peng J, Murugan M, Wang X, Eyo UB, Sun D, Ren Y, DiCicco-Bloom E, Young W, Dong H, Wu LJ. (2016) Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivty after peripheral nerve injury. Cell Rep. 2016 Jun 29. pii: S2211- 1247(16)30758-6. doi: 10.1016/j.celrep.2016.06.018. [Epub ahead of print]
  • Mony TJ, Lee JW, Dreyfus C, DiCicco-Bloom E., Lee HJ. (2016) Valrpoic acid exposure during early postnatal gliogenesis leads to autistic-like behaviors in rats. Clin Psychopharmacol Neurosci. 2016 Nov 30;14(4):338-344. doi:10.9758/cpn.2016.14.4.338.
  • Fernandes DJ, Ellegood J, Askalan R, Blakely RD, DiCicco-Bloom E., Egan SE, Osborne LR, Powell CM, Raznahan A, Robins DM, Salter MW, Sengar AS, Veenstra-VenderWeele J, Lerch JP. (2017) Spatial gene expression analysis of neuroanatomical differences in mouse models. Neuroimage. 2017 Sep 4;163:220- 230. doi: 10.1016/j.neuroimage.2017.08.065. [Epub ahead of print]
  • Gupta A, Li X, DiCicco-Bloom E., Bello NT (2018) Altered salt taste response and increased tongue epithelium Scnna1 expression in adult Engrailed-2 null mice. Physiology & Behavior 2018 Jun 25. pii: S0031-9384(18)30395-0. doi: 10.1016/j.physbeh.2018.06.030. [Epub ahead of print] PMID: 29953887
  • Williams M, Prem S, Zhou X, Matteson P, Leung L, Lu CW, Pang Z, Brzustowicz L, Millonig JH, DiCicco-Bloom E. (2018) Rapid Detection of Neurodevelopmental Phenotypes In Human Neural Precursor Cells (NPCs). J Vis Exp. 2018 Mar 2;(133). doi: 10.3791/56628. PMID: 29553565
  • Connacher RJ, DiCicco-Bloom E., Millonig JH. (2018) Using human induced neural precursor cells to define early neurodevelopmental defects in syndromic and idiopathic autism. Current Pharmacology Reports. https://doi.org/10.1007/s40495-018-0155-0.

Books

  • DiCicco-Bloom, E., Obiorah M. Neural Development and Neurogenesis. In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Tenth Edition, Ed. B.J. Sadock, V.A. Sadock, P. Ruiz, Wolters Kluwer, pages 39-61, Philadelphia, 2017
  • Rossman, I.T. and DiCicco-Bloom, E. (2008) Chapter 1. ENGRAILED 2 and Cerebellar Development in the Pathogenesis of Autism Spectrum Disorders. In: Autism: Current Theories and Evidence. Ed. A. W. Zimmerman, Humana Press, a part of Springer Scientific Business Media, LLC, Totowa, NJ, page 3-40.