1972 - Ph.D. Univ. of Colorado.
1978 - Present, Lecturer, Senior Lecturer; Associate Professor; Professor.
1991 - Present
, Professor (Adjunct); Department of Pharmacology, Duke University Medical School, Durham, North Carolina, USA, Email: email@example.com
Ascertaining in the mouse and chick models the mechanisms of neural and behavioral birth defects induced by various agents, mainly organophosphates and heroin, and their reversal with mesenchymal and neural stem cell (MSC, NSC) therapies; understanding the mechanisms by which the transplanted cells exert their therapeutic action.
Currently, we are similarly working towards understanding neurobehavioral birth defects induced by parental (paternal and/or maternal-preconception) exposure. Most probably via the epigenetic genomic imprinting mechanisms. Again, with reversing the deficits with stem cell transplantation.
In the mouse model, the study of the mechanisms focuses on behaviors related to the septohippocampal cholinergic innervation (Morris and eight-arm mazes). Our hypothesis is that abolishment in the hippocampus of cholinergic receptor-induced translocation/activation of PKCγ represents a principal component in the mechanism by which various substances induces neurobehavioral birth defects.
Our parallel chick model, which controls for maternal confounds, involves perturbation by the teratogen of imprinting related to defects where the mechanism is again abolishment of translocation/activation of PKCγ in the IMHV (IMM) nucleus.
In both models we are promoting the novel hypothesis that one major mechanism by which stem cells exert their therapeutic action is by inducing neurogenesis, i.e. proliferation of endogenous precursors.
In both models the changes in synaptic function may be regulated by the teratogen- induced epigenetic alterations.
Research milestones old and new (text citations listed at the bottom of the website):
- Being one of the founders of the modern Behavioral Teratology, thus expanded the concept by introducing the study of the mechanisms of the defects termed “Neurobehavioral Teratology” (Yanai 1984, Yaniv et al 2004).
- Developing the model for the reversal of neurobehavioral teratogenicity, in mice, by way of neural grafting (Steingart et al 2000, Yanai & Pick 1988).
- Reversal of neurobehavioral teratogenicity in mice by manipulations of the A10 regulating neural pathways (Yanai et al 1987, Yanai et al 1989).
- Reversal of neurobehavioral teratogenicity, in mice, via nicotine therapy (Beer et al 2005).
- Reversal of neurobehavioral teratogenicity, in mice, via transplantation of various types of stem cells (Ben-Shaanan et al 2008, Izrael et al 2004, Katz et al 2008, Turgeman et al 2011, Yanai et al 2005, Yanai et al 1995a).
- The establishment of models for the reversal of neurobehavioral deficits in the avian: a. Parkinson’s disease in the adult chicken (Yanai et al 1995b), b. reversal of neurobehavioral teratogenicity in a chick embryo model (Pinkas et al 2013).
- Establishing the principle that one major mechanism by which stem cells exert their therapeutic effect is the induction of neurogenesis (Ben-Shaanan et al 2008, Pinkas et al 2013).
An unexpected error has occurred.
Pregnant female mice were exposed to heroin, organophosphate or other substances. Their offspring showed, upon maturity, an abolishment of cholinergic receptor-induced activation/translocation of PKCγ in the septohippocampal cholinergic innervation, paralleled with defects in the hippocampus-related Morris and eight-arm maze behaviors.
Understanding the synaptic mechanism of the behavioral defects enabled reversal of the neurobehavioral teratogenicity using the various therapies described above.
Further studies suggest that one major mechanism by which the transplanted cells exerted their therapeutic action is by the induction of neurogenesis and synaptogenesis in the teratogen-impaired brain. Further studies demonstrated impairment of neurogenesis (doublecortin and neurogenesis-related genes) after prenatal exposure to teratogen (chlorpyrifos). Transplantation of MSC restored normal neurogenesis.
In the chick model, incubated eggs were injected with various teratogens. The hatched chicks showed marked defects in their imprinting behavior, which was correlated with abolishment of cholinergic-induced activation/translocation of PKCγ in their IMHV (IMM) nucleus. Additionally, neurogenesis was impaired as attested to by reduced doublecortin labeling and neurogenesis-related genes. Stem cells transplanted to the chick embryo via the blood vessels attached to the chorio-allantoic membrane reach the embryonic brain and restored normal neurogenesis.
Currently, we are testing the hypothesis, in both models, that the changes described may be regulated by the teratogen-induced epigenetic alterations.
The study of the reversal of heroin and chlorpyrifos (an organophosphate)-induced neurobehavioral teratogenicity serves as examples: NSC derived from normal developing brains (Fig. 1) were grafted into the hippocampus of mice offspring who were exposed prenatally to the teratogens and showed hippocampus related defects in behavior and PKC activation/translocation.
Fig. 1 Differentiation of ES-NSC dissociated precursor cells into neural lineage cells.
A. ES-NSC grown in the presence of the growth factors EGF and bFGF are positive for neural marker- Nestin. B-D. Growth factor removal promoted the differentiation of ES-NSC into neurons, oligodendrocyte and astrocytes; B. NF160 positive differentiated neurons, B’. High proportion of NF positive cells exhibit cholinergic marker ChAT. C. O4 positive oligodendrocytes. D. GFAP positive astrocytes. E. PCR Expression of Neural genes with and without growth factor. Each band of the neural lineage genes tested was normalized in relation to the house keeping gene GAPDH. Size bars: A-D: 100 μm. F. Quantitative representation of the gene expression findings with and without (w/o) growth factors (GF).
The transplanted cells survived and differentiated in the host hippocampus as shown in Fig. 2. Offspring exposed prenatally to heroin had at maturity deficits in Morris maze behavior (A) and in the mechanistically-related absolute abolishment of cholinergic receptor-induced activation/translocation of hippocampal PKCγ (B). Transplantation of NSC into the impaired hippocampus reversed the neurobehavioral defects (Fig. 3).
Yanai, J., and C.G. Pick. Neuron transplantation reverses phenobarbital-induced behavioral birth defects in mice. Int. J. Dev. Neurosci., 6:409-416 (1988).
Yanai, J., U. Laxer, C. G. Pick and D. Trombka. Dopaminergic denervation reverses behavioral deficits induced by prenatal exposure to phenobarbital. Dev. Brain Research, 48:255-261 (1989).
Yanai, J., T. Doetchman, N. Laufer, J. Maslaton, S. Mor-Yosef, M. Shani and D. Sofer. Embryonic cultures but not embryos transplanted to the mouse's brain grow rapidly without immunosuppression. Int. Journal of Neuroscience 81:21-26 (1995).
Yanai, J., W. Silverman and D. Shamir. An avian model for the reversal of 6-hydroxydopamine induced rotating behavior by neural grafting. Neuroscience Letters 187:153-156 (1995).
Steingart, R. A., W. F. Silverman, S. Barron, T. A. Slotkin, Y. Awad and J. Yanai. Neural grafting reverses prenatal drug-induced alterations in hippocampal PKC and related behavioral deficits. Dev. Brain. Research, 125:9-19 (2000).
Yaniv, S. P., Z. Naor and J. Yanai. Prenatal heroin exposure alters cholinergic receptor stimulated translocation and basal levels of the PKCbII and PKCg isoforms. Brain Research Bulletin, 63: 339–349 (2004).
Izrael, M., E. A. Van der Zee, T. A. Slotkin and J. Yanai. Cholinergic Synaptic Signaling Mechanisms Underlying Behavioral Teratogenicity: Effects of Nicotine, Chlorpyrifos and Heroin Converge on PKC Translocation in the IMHV and on Imprinting Behavior in an Avian Model J. Neuroscience Research, 78:499–507 (2004).
Beer, A., T. A. Slotkin, F. J. Seidler and J. Yanai. Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital. Neuropsychopharmacology, 30: 156–165 (2005).
Katz S., T. Ben-Hur , T. L. Ben-Shaanan, and J. Yanai. Reversal of heroin neurobehavioral teratogenicity by grafting of neural progenitors. Journal of Neurochemistry, 104:38-49 (2008).
Ben-Shaanan T. L., T. Ben-Hur, and J. Yanai. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Molecular Psychiatry, 13: 222-231 (2008).
Kazma, M., M. Izrael, M. Revel, J. Chebath and J. Yanai. Survival, differentiation and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells. Journal of Neuroscience Research 88(2): 315-323 (2009).
Yanai, J., A. Pinkas, F. Seidler, I. Ryde, E. Van der Zee and T. Slotkin. Neurobehavioral teratogenicity of sarin in an avian model. Neurotoxicology and Teratology, 31(6): 406-412 (2009).
Hamisha, K. N., M. Tfilin, J. Yanai and G. Turgeman. Mesenchymal stem cells can prevent alterations in behavior and neurogenesis induced by Aß25-35 administration. J. Mol. Neurosci. 55: 1006-1013 (2015)
Pinkas A., G. Turgeman, S. Tayeb and J. Yanai. An avian model for ascertaining the mechanisms of organophosphate neuroteratogenicity and its therapy with mesenchymal stem cell transplantation. Neurotoxicology and teratology, Neurotoxicology and teratology 50: 73-81 (2015).
Ornoy, A., L. Weinstein-Fudim, M. Tfilin, Z. Ergaz, J. Yanai, M. Szyf, and G. Turgeman. S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice. Neurotoxicology and teratology 71:64-74 (2019).
Yanai, J., M. Vigoda, and A. Ornoy. Reversal of Neurobehavioral Teratogenicity in animal models and human: Three Decades of Progress. Brain Research Bulletin 150: 328–342 (2019).