Central Nervous System; Neuroglia; Neurons; Nose; Gene Expression Profiling
Neurosurgery: Greer Lab
We study mechanisms mediating the complex pathfinding and
synaptogenesis of axons and dendrites during early development and how
those mechanisms may degrade during aging. In the olfactory system,
~1,000 subpopulations of sensory neurons express different odor
receptors. The sensory neuron axons segregate in the olfactory bulb
based on odor receptor expression, producing a highly specific molecular
map. Understanding the molecular basis of this segregation of axons is
one of our primary goals.
In parallel, we study the targeting and differentiation of dendrites to understand the mechanisms that regulate their highly specific interactions with small subsets of the sensory neuron axons. Unique to the olfactory system, ongoing adult neurogenesis generates new populations of sensory neurons in the olfactory epithelium and interneurons centrally. The molecular differentiation and integration of these adult generated neurons into synaptic circuits is an ongoing interest in the lab.
Extensive Research Description
Current Research Program
A major goal of my laboratory is understanding the basic mechanisms that contribute to the establishment of orderly topographic maps within the CNS, during both normal development and during regenerative events following injury or disease. We have been focusing our efforts on the olfactory system, in part because of the complexity of the map between the olfactory epithelium and the olfactory bulb. Axons sort into 1,000 functional subsets that are targeted with high specificity to olfactory bulb glomeruli.
Using both in vivo and in vitro models, we are currently isolating several mechanisms that may contribute to this complex reorganization including laminin, tenascin and the expression of putative odor receptors in growth cones. In related studies we continue to characterize a unique population of glial cells, ensheathing cells, found in the olfactory nerve. While elsewhere in the mature CNS glia are an impediment to axon growth, the ensheathing cell glia support axon extension and targeting throughout life.
We recently demonstrated that the growth promoting effects of ensheathing cells are not limited to olfactory receptor neurons but are also seen in other populations of neurons. Particularly exciting, our recent studies demonstrate that the ensheathing cells remain pluri-potential and that when implanted into demyelinated spinal cord can adopt a myelinating phenotype which remyelinates the axons and contributes to a restoration of normal conduction velocities.
In parallel studies we are examining the molecular and synaptic organization of the olfactory bulb glomeruli. Using RT-PCR we are mapping the distribution of subsets of olfactory receptor cell axons in glomeruli to gain insights into the topography of odor-ligand maps in the olfactory bulb. In addition, working with colleagues, we are using a GFP tag to test hypotheses regarding the specificity of synaptic organization within glomeruli. Second, using antibodies synaptic vesicle related proteins and confocal microscopy we have begun to describe a hitherto unrecognized segregation of local and projection synaptic circuits in the glomeruli.
It may be that this segregation underlies the lateral inhibitory systems that are believed to be operative in the olfactory system. Beyond my colleagues in Neurosurgery, I maintain active collaborations with the following Departments at Yale: Neurology, Neurobiology, Anesthesiology and Ophthamology. In addition, I have collaborative studies with members of the faculty at Columbia University, Emory University, The Rockefeller, University of Maryland and University of Colorado.
Increasingly, the neurological sciences are focusing on intervention strategies that will both limit the debilitating consequences of injury/disease as well as increase the probability of successful regeneration of pathways and connections in the CNS. In order to facilitate these processes it is necessary for us to understand the molecular and cellular events operative during axon extension, target selection and synapse formation. The studies described above directly assess those questions and, particularly in the case of the ensheathing cells, offer the possibility of clinical application in the near future.
Fate mapping of olfactory bulb projection neurons
The role of axon:axon adhesion in establishing sensory maps
Cell surface and diffusible molecules influencing the extension and convergence of axons
The timing and molecular mechanisms mediating the development of 3-layer piriform cortex
Segregated labeling of olfactory bulb projection neurons based on their birthdates.
Imamura F, Greer CA. Segregated labeling of olfactory bulb projection neurons based on their birthdates. The European Journal Of Neuroscience 2015, 41:147-56. 2015
Dendrodendritic synapses in the mouse olfactory bulb external plexiform layer.
Bartel DL, Rela L, Hsieh L, Greer CA. Dendrodendritic synapses in the mouse olfactory bulb external plexiform layer. The Journal Of Comparative Neurology 2015, 523:1145-61. 2015
Nonsensory target-dependent organization of piriform cortex.
Chen CF, Zou DJ, Altomare CG, Xu L, Greer CA, Firestein SJ. Nonsensory target-dependent organization of piriform cortex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111:16931-6. 2014
Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons.
Lepousez G, Nissant A, Bryant AK, Gheusi G, Greer CA, Lledo PM. Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111:13984-9. 2014
Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells.
Imamura F, Greer CA. Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells. Molecular And Cellular Neurosciences 2013, 54:58-70. 2013
Timing of neurogenesis is a determinant of olfactory circuitry.
Imamura F, Ayoub AE, Rakic P, Greer CA. Timing of neurogenesis is a determinant of olfactory circuitry. Nature Neuroscience 2011, 14:331-7. 2011
Developmental dynamics of piriform cortex.
Sarma AA, Richard MB, Greer CA. Developmental dynamics of piriform cortex. Cerebral Cortex (New York, N.Y. : 1991) 2011, 21:1231-45. 2011
Age-induced disruption of selective olfactory bulb synaptic circuits.
Richard MB, Taylor SR, Greer CA. Age-induced disruption of selective olfactory bulb synaptic circuits. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107:15613-8. 2010
Dendritic branching of olfactory bulb mitral and tufted cells: regulation by TrkB.
Imamura F, Greer CA. Dendritic branching of olfactory bulb mitral and tufted cells: regulation by TrkB. PloS One 2009, 4:e6729. 2009
Synaptic integration of adult-generated olfactory bulb granule cells: basal axodendritic centrifugal input precedes apical dendrodendritic local circuits.
Whitman MC, Greer CA. Synaptic integration of adult-generated olfactory bulb granule cells: basal axodendritic centrifugal input precedes apical dendrodendritic local circuits. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2007, 27:9951-61. 2007
Full List of PubMed Publications
- Piantanida AP, Acosta LE, Brocardo L, Capurro C, Greer CA, Rela L: Selective Cre-mediated gene deletion identifies connexin 43 as the main connexin channel supporting olfactory ensheathing cell networks. J Comp Neurol. 2019 May 1; 2019 Jan 21. PMID: 30628061
- Katrancha SM, Shaw JE, Zhao AY, Myers SA, Cocco AR, Jeng AT, Zhu M, Pittenger C, Greer CA, Carr SA, Xiao X, Koleske AJ: Trio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits. Cell Rep. 2019 Mar 5. PMID: 30840899
- Martin-Lopez E, Ishiguro K, Greer CA: The Laminar Organization of Piriform Cortex Follows a Selective Developmental and Migratory Program Established by Cell Lineage. Cereb Cortex. 2019 Jan 1. PMID: 29136113
- Martin-Lopez E, Meller SJ, Greer CA: Development of piriform cortex interhemispheric connections via the anterior commissure: progressive and regressive strategies. Brain Struct Funct. 2018 Dec; 2018 Aug 24. PMID: 30141078
- Pyrski M, Tusty M, Eckstein E, Oboti L, Rodriguez-Gil DJ, Greer CA, Zufall F: P/Q Type Calcium Channel Cav2.1 Defines a Unique Subset of Glomeruli in the Mouse Olfactory Bulb. Front Cell Neurosci. 2018; 2018 Sep 4. PMID: 30233329
- Levy AD, Xiao X, Shaw JE, Sudarsana Devi SP, Katrancha SM, Bennett AM, Greer CA, Howe JR, Machida K, Koleske AJ: Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell Rep. 2018 Aug 7. PMID: 30089263
- Omar MH, Kerrisk Campbell M, Xiao X, Zhong Q, Brunken WJ, Miner JH, Greer CA, Koleske AJ: CNS Neurons Deposit Laminin α5 to Stabilize Synapses. Cell Rep. 2017 Oct 31. PMID: 29091766
- Finger TE, Bartel DL, Shultz N, Goodson NB, Greer CA: 5HTR3A-driven GFP labels immature olfactory sensory neurons. J Comp Neurol. 2017 May 1; 2017 Feb 27. PMID: 28152579
- Kawasawa YI, Salzberg AC, Li M, Šestan N, Greer CA, Imamura F: RNA-seq analysis of developing olfactory bulb projection neurons. Mol Cell Neurosci. 2016 Jul; 2016 Apr 9. PMID: 27073125
- Rela L, Piantanida AP, Bordey A, Greer CA: Voltage-dependent K+ currents contribute to heterogeneity of olfactory ensheathing cells. Glia. 2015 Sep; 2015 Apr 9. PMID: 25856239
- Bartel DL, Rela L, Hsieh L, Greer CA: Dendrodendritic synapses in the mouse olfactory bulb external plexiform layer. J Comp Neurol. 2015 Jun 1; 2015 Feb 17. PMID: 25420934
- Rodriguez-Gil DJ, Bartel DL, Jaspers AW, Mobley AS, Imamura F, Greer CA: Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons. Proc Natl Acad Sci U S A. 2015 May 5; 2015 Apr 20. PMID: 25902488
- Imamura F, Greer CA: Segregated labeling of olfactory bulb projection neurons based on their birthdates. Eur J Neurosci. 2015 Jan; 2014 Nov 13. PMID: 25393912
- Chen CF, Zou DJ, Altomare CG, Xu L, Greer CA, Firestein SJ: Nonsensory target-dependent organization of piriform cortex. Proc Natl Acad Sci U S A. 2014 Nov 25; 2014 Nov 10. PMID: 25385630
- Lepousez G, Nissant A, Bryant AK, Gheusi G, Greer CA, Lledo PM: Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons. Proc Natl Acad Sci U S A. 2014 Sep 23; 2014 Sep 4. PMID: 25189772
- Mobley AS, Rodriguez-Gil DJ, Imamura F, Greer CA: Aging in the olfactory system. Trends Neurosci. 2014 Feb; 2013 Dec 19. PMID: 24361044
- Mobley AS, Bryant AK, Richard MB, Brann JH, Firestein SJ, Greer CA: Age-dependent regional changes in the rostral migratory stream. Neurobiol Aging. 2013 Jul; 2013 Feb 15. PMID: 23419702
- Imamura F, Greer CA: Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells. Mol Cell Neurosci. 2013 May; 2013 Jan 22. PMID: 23353076
- Kerrisk ME, Greer CA, Koleske AJ: Integrin α3 is required for late postnatal stability of dendrite arbors, dendritic spines and synapses, and mouse behavior. J Neurosci. 2013 Apr 17. PMID: 23595732
- Rodriguez-Gil DJ, Hu W, Greer CA: Dishevelled proteins are associated with olfactory sensory neuron presynaptic terminals. PLoS One. 2013; 2013 Feb 20. PMID: 23437169
- Warren MS, Bradley WD, Gourley SL, Lin YC, Simpson MA, Reichardt LF, Greer CA, Taylor JR, Koleske AJ: Integrin β1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior. J Neurosci. 2012 Feb 22. PMID: 22357865
- Sarma AA, Richard MB, Greer CA: Developmental dynamics of piriform cortex. Cereb Cortex. 2011 Jun; 2010 Nov 1. PMID: 21041199
- Imamura F, Ayoub AE, Rakic P, Greer CA: Timing of neurogenesis is a determinant of olfactory circuitry. Nat Neurosci. 2011 Mar; 2011 Feb 6. PMID: 21297629
- Shepherd GM, Greer CA, Mazzarello P, Sassoè-Pognetto M: The first images of nerve cells: Golgi on the olfactory bulb 1875. Brain Res Rev. 2011 Jan 7; 2010 Nov 13. PMID: 20940020
- Pluznick JL, Rodriguez-Gil DJ, Hull M, Mistry K, Gattone V, Johnson CA, Weatherbee S, Greer CA, Caplan MJ: Renal cystic disease proteins play critical roles in the organization of the olfactory epithelium. PLoS One. 2011; 2011 May 13. PMID: 21614130
- Miller AM, Treloar HB, Greer CA: Composition of the migratory mass during development of the olfactory nerve. J Comp Neurol. 2010 Dec 15. PMID: 21031554
- Mobley AS, Miller AM, Araneda RC, Maurer LR, Müller F, Greer CA: Hyperpolarization-activated cyclic nucleotide-gated channels in olfactory sensory neurons regulate axon extension and glomerular formation. J Neurosci. 2010 Dec 8. PMID: 21147989
- Richard MB, Taylor SR, Greer CA: Age-induced disruption of selective olfactory bulb synaptic circuits. Proc Natl Acad Sci U S A. 2010 Aug 31; 2010 Aug 2. PMID: 20679234
- Miller AM, Maurer LR, Zou DJ, Firestein S, Greer CA: Axon fasciculation in the developing olfactory nerve. Neural Dev. 2010 Aug 19; 2010 Aug 19. PMID: 20723208
- Rodriguez-Gil DJ, Treloar HB, Zhang X, Miller AM, Two A, Iwema C, Firestein SJ, Greer CA: Chromosomal location-dependent nonstochastic onset of odor receptor expression. J Neurosci. 2010 Jul 28. PMID: 20668191
- Rela L, Bordey A, Greer CA: Olfactory ensheathing cell membrane properties are shaped by connectivity. Glia. 2010 Apr 15. PMID: 19998494
- Whitman MC, Greer CA: Adult neurogenesis and the olfactory system. Prog Neurobiol. 2009 Oct; 2009 Jul 15. PMID: 19615423
- Whitman MC, Fan W, Rela L, Rodriguez-Gil DJ, Greer CA: Blood vessels form a migratory scaffold in the rostral migratory stream. J Comp Neurol. 2009 Sep 10. PMID: 19575445
- Imamura F, Greer CA: Dendritic branching of olfactory bulb mitral and tufted cells: regulation by TrkB. PLoS One. 2009 Aug 25; 2009 Aug 25. PMID: 19707543
- Fletcher ML, Masurkar AV, Xing J, Imamura F, Xiong W, Nagayama S, Mutoh H, Greer CA, Knöpfel T, Chen WR: Optical imaging of postsynaptic odor representation in the glomerular layer of the mouse olfactory bulb. J Neurophysiol. 2009 Aug; 2009 May 27. PMID: 19474178
- Treloar HB, Ray A, Dinglasan LA, Schachner M, Greer CA: Tenascin-C is an inhibitory boundary molecule in the developing olfactory bulb. J Neurosci. 2009 Jul 29. PMID: 19641104
- Rodriguez-Gil DJ, Treloar HB, Miller A, Two A, Iwema C, Greer CA: Onset of odorant receptors. Ann N Y Acad Sci. 2009 Jul. PMID: 19686100
- Pluznick JL, Zou DJ, Zhang X, Yan Q, Rodriguez-Gil DJ, Eisner C, Wells E, Greer CA, Wang T, Firestein S, Schnermann J, Caplan MJ: Functional expression of the olfactory signaling system in the kidney. Proc Natl Acad Sci U S A. 2009 Feb 10; 2009 Jan 27. PMID: 19174512
- Rodriguez-Gil D, Greer CA: Non-exclusive exclusion (Commentary on Capello et al.). Eur J Neurosci. 2009 Feb; 2008 Feb 6. PMID: 19200069
- Rodriguez-Gil DJ, Greer CA: Wnt/Frizzled family members mediate olfactory sensory neuron axon extension. J Comp Neurol. 2008 Nov 20. PMID: 18803244
- Maresh A, Rodriguez Gil D, Whitman MC, Greer CA: Principles of glomerular organization in the human olfactory bulb--implications for odor processing. PLoS One. 2008 Jul 9; 2008 Jul 9. PMID: 18612420
- Shay EL, Greer CA, Treloar HB: Dynamic expression patterns of ECM molecules in the developing mouse olfactory pathway. Dev Dyn. 2008 Jul. PMID: 18570250
- Sfakianos MK, Eisman A, Gourley SL, Bradley WD, Scheetz AJ, Settleman J, Taylor JR, Greer CA, Williamson A, Koleske AJ: Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior. J Neurosci. 2007 Oct 10. PMID: 17928439
- Shepherd GM, Chen WR, Willhite D, Migliore M, Greer CA: The olfactory granule cell: from classical enigma to central role in olfactory processing. Brain Res Rev. 2007 Oct; 2007 Mar 16. PMID: 17434592
- Whitman MC, Greer CA: Synaptic integration of adult-generated olfactory bulb granule cells: basal axodendritic centrifugal input precedes apical dendrodendritic local circuits. J Neurosci. 2007 Sep 12. PMID: 17855609
- Whitman MC, Greer CA: Adult-generated neurons exhibit diverse developmental fates. Dev Neurobiol. 2007 Jul. PMID: 17565001
- Akins MR, Benson DL, Greer CA: Cadherin expression in the developing mouse olfactory system. J Comp Neurol. 2007 Apr 1. PMID: 17278136
- Akins MR, Greer CA: Axon behavior in the olfactory nerve reflects the involvement of catenin-cadherin mediated adhesion. J Comp Neurol. 2006 Dec 20. PMID: 17072833
- Zhou Z, Xiong W, Zeng S, Xia A, Shepherd GM, Greer CA, Chen WR: Dendritic excitability and calcium signalling in the mitral cell distal glomerular tuft. Eur J Neurosci. 2006 Sep. PMID: 17004926
- Willhite DC, Nguyen KT, Masurkar AV, Greer CA, Shepherd GM, Chen WR: Viral tracing identifies distributed columnar organization in the olfactory bulb. Proc Natl Acad Sci U S A. 2006 Aug 15; 2006 Aug 8. PMID: 16895993
- Akins MR, Greer CA: Cytoskeletal organization of the developing mouse olfactory nerve layer. J Comp Neurol. 2006 Jan 10. PMID: 16320244
- Whitley M, Treloar H, De Arcangelis A, Georges Labouesse E, Greer CA: The alpha6 integrin subunit in the developing mouse olfactory bulb. J Neurocytol. 2005 Mar. PMID: 16374711
- Treloar HB, Uboha U, Jeromin A, Greer CA: Expression of the neuronal calcium sensor protein NCS-1 in the developing mouse olfactory pathway. J Comp Neurol. 2005 Feb 7. PMID: 15611992
- Beech RD, Cleary MA, Treloar HB, Eisch AJ, Harrist AV, Zhong W, Greer CA, Duman RS, Picciotto MR: Nestin promoter/enhancer directs transgene expression to precursors of adult generated periglomerular neurons. J Comp Neurol. 2004 Jul 12. PMID: 15176089
- Akiyama Y, Lankford K, Radtke C, Greer CA, Kocsis JD: Remyelination of spinal cord axons by olfactory ensheathing cells and Schwann cells derived from a transgenic rat expressing alkaline phosphatase marker gene. Neuron Glia Biol. 2004 Feb. PMID: 16799702
- Lipscomb BW, Treloar HB, Klenoff J, Greer CA: Cell surface carbohydrates and glomerular targeting of olfactory sensory neuron axons in the mouse. J Comp Neurol. 2003 Dec 1. PMID: 14574677
- Treloar HB, Gabeau D, Yoshihara Y, Mori K, Greer CA: Inverse expression of olfactory cell adhesion molecule in a subset of olfactory axons and a subset of mitral/tufted cells in the developing rat main olfactory bulb. J Comp Neurol. 2003 Apr 14. PMID: 12619073
- Ma M, Grosmaitre X, Iwema CL, Baker H, Greer CA, Shepherd GM: Olfactory signal transduction in the mouse septal organ. J Neurosci. 2003 Jan 1. PMID: 12514230
- Wang X, Chun SJ, Treloar H, Vartanian T, Greer CA, Strittmatter SM: Localization of Nogo-A and Nogo-66 receptor proteins at sites of axon-myelin and synaptic contact. J Neurosci. 2002 Jul 1. PMID: 12097502
- Au WW, Treloar HB, Greer CA: Sublaminar organization of the mouse olfactory bulb nerve layer. J Comp Neurol. 2002 Apr 22. PMID: 11920721
- Lipscomb BW, Treloar HB, Greer CA: Cell surface carbohydrates reveal heterogeneity in olfactory receptor cell axons in the mouse. Cell Tissue Res. 2002 Apr; 2002 Mar 26. PMID: 12012202
- Treloar HB, Feinstein P, Mombaerts P, Greer CA: Specificity of glomerular targeting by olfactory sensory axons. J Neurosci. 2002 Apr 1. PMID: 11923411
- Lipscomb BW, Treloar HB, Greer CA: Novel microglomerular structures in the olfactory bulb of mice. J Neurosci. 2002 Feb 1. PMID: 11826106