Eric Olson, PhD
RESEARCH PROGRAMS AND AFFILIATIONS
Cellular and molecular mechanisms of cerebral cortex development.
Lissencephaly / neuronal migration disorders; Dendritogenesis and early cortical wiring; Reelin-Dab1 signaling; Adaptor proteins; Fetal Alcohol Syndrome; Intellectual disability
Our laboratory seeks to understand the fundamental mechanisms underlying the migration and dendrite initiation in the developing mammalian cortex.
The mature cortical neuron receives synaptic input via the apical dendrite and integrates this input prior to firing an action potential. Unsurprisingly, disruption of dendritic growth and function underlie many neurological disorders including intellectual disability, epilepsy and autism.
Ontogeny of the apical dendrite: Using multiphoton microscopy we have recently documented that the apical dendrite emerges by direct transformation of the leading process of the migrating neuron. This transformation occurs at the end of the migration route as the leading process contacts the marginal zone of the developing cortex. During this ~2 hr transformation, the leading process grows 2.5 fold in size and increases its branching 3.5 fold (O'Dell et al., 2015). Branches in the leading process impede migration and therefore a stable branch point may constitute the "stop signal" for neuronal migration. This would suggest that neurons migrate until they encounter dendritic growth cues.
How do neurons respond to the secreted glycoprotein Reelin? Using this multiphoton approach we have examined a mouse model of intellectual disability called the reeler mouse that has a mutation in a gene called Reln (Reelin). Reelin is a glycoprotein protein secreted by CR neurons in the region of dendritic initiation and growth. Absent Reelin, the dendritic filopodia retracted away from the marginal zone, the cells became dysmorphic and the dendrites were tangentially oriented. Injection of Reelin protein was able to rescue this dysmorphology and the dendrites became radially oriented with a pial-directed apical dendrite. (For more information see Nichols et al., 2010; O'Dell et al., 2012; O'Dell et al., 2015).
Questions presently addressed in the laboratory:
What are the other extracellular cues regulating dendritic polarized dendritic growth? Reelin is likely a permissive signal and works in conjunction with multiple other signaling pathways to mediate its biological effect. We are identifying other cues that cooperate with Reelin to mediate this stabilization and polarization of the apical dendrite.
Does ethanol exposure disrupt Reelin-signaling? As part of an NIAAA funded center (DEARC) we are examining the possibility that ethanol exposure disrupts dendritic growth and Reelin-signaling during development. This disruption could contribute to the intellectual disability observed with Fetal Alcohol Syndrome (FAS). (For more see Powrozek et al., 2012; Olson, 2014).
Control of gene expression during dendritic initiation: In a prior study (Cameron et al., 2012) we found that >220 genes that were upregulated more than 3-fold during the area encompassing the end of migration and the formation of the dendrite. At least half of the validated 3-fold up genes have been associated with neurological disease including autism and intellectual disability. This finding underscores not only the extreme dynamism of dendritogenic period, involving the cessation of migration and the elaboration of both dendrites and axons, but also the potential relevance to neurological disease. What triggers this increase in gene expression at the end of the migration route?
Focal adhesion adaptors: In collaboration with Dr. Chris Turner (SUNY Upstate), we have generated conditional knockout mice for the focal adhesion adaptor proteins Paxillin and Hic5 and are examining their role in cortical neuron migration and dendritogenesis.
Rashid M, Belmont J, Carpenter D, Turner CE, Olson EC. Neural-specific deletion of the focal adhesion adaptor protein paxillin slows migration speed and delays cortical layer formation. Development. 2017 Nov 1;144(21):4002-4014. doi: 10.1242/dev.147934. Epub 2017 Sep 21.PMID:28935710
Lammert DB, Middleton FA, Pan J, Olson EC, Howell BW.The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression. J Neurochem. 2017 Jul;142(1):89-102. doi: 10.1111/jnc.14045. Epub 2017 May 18. PMID:28419454
Goreczny GJ, Ouderkirk-Pecone JL, Olson EC, Krendel M, Turner CE. Hic-5 remodeling of the stromal matrix promotes breast tumor progression. Oncogene. 2017 May 11;36(19):2693-2703. doi: 10.1038/onc.2016.422. Epub 2016 Nov 28.PMID:27893716
O'Dell RS, Cameron DA, Zipfel WR, Olson EC. Reelin Prevents Apical Neurite Retraction during Terminal Translocation and Dendrite Initiation. J Neurosci. 2015 Jul 29;35(30):10659-74. doi: 10.1523/JNEUROSCI.1629-15.2015.PMID:26224852 (Cover Article).
Olson EC. Analysis of preplate splitting and early cortical development illuminates the biology of neurological disease. Front Pediatr. 2014 Nov 11;2:121. doi: 10.3389/fped.2014.00121. eCollection 2014. Review.PMID:25426475
Dixit R, Wilkinson G, Cancino GI, Shaker T, Adnani L, Li S, Dennis D, Kurrasch D, Chan JA, Olson EC, Kaplan DR, Zimmer C, Schuurmans C. Neurog1 and Neurog2 control two waves of neuronal differentiation in the piriform cortex. J Neurosci. 2014 Jan 8;34(2):539-53. doi: 10.1523/JNEUROSCI.0614-13.2014.PMID:24403153
Schulte JD, Srikanth M, Das S, Zhang J, Lathia JD, Yin L, Rich JN, Olson EC, Kessler JA, Chenn A. Cadherin-11 regulates motility in normal cortical neural precursors and glioblastoma. PLoS One. 2013 Aug 7;8(8):e70962. doi: 10.1371/journal.pone.0070962. eCollection 2013.PMID:23951053
Nichols AJ, O'Dell RS, Powrozek TA, Olson EC. Ex utero electroporation and whole hemisphere explants: a simple experimental method for studies of early cortical development. J Vis Exp. 2013 Apr 3;(74). doi: 10.3791/50271.PMID:23609059
Powrozek TA, Olson EC. Ethanol-induced disruption of Golgi apparatus morphology, primary neurite number and cellular orientation in developing cortical neurons. Alcohol. 2012 Nov;46(7):619-27. doi: 10.1016/j.alcohol.2012.07.003. Epub 2012 Jul 25.PMID:22840816
O'Dell RS, Ustine CJ, Cameron DA, Lawless SM, Williams RM, Zipfel WR, Olson EC. Layer 6 cortical neurons require Reelin-Dab1 signaling for cellular orientation, Golgi deployment, and directed neurite growth into the marginal zone. Neural Dev. 2012 Jul 7;7:25. doi: 10.1186/1749-8104-7-25.PMID:22770513 (Highly Accessed)
Cameron DA, Middleton FA, Chenn A, Olson EC. Hierarchical clustering of gene expression patterns in the Eomes + lineage of excitatory neurons during early neocortical development. BMC Neurosci. 2012 Aug 1;13:90. doi: 10.1186/1471-2202-13-90.PMID:22852769 (Highly Accessed)
Matsuki T, Matthews RT, Cooper JA, van der Brug MP, Cookson MR, Hardy JA, Olson EC, Howell BW. Reelin and stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell. 2010 Nov 24;143(5):826-36. doi: 10.1016/j.cell.2010.10.029.PMID:21111240
Mutch CA, Schulte JD, Olson E, Chenn A. Beta-catenin signaling negatively regulates intermediate progenitor population numbers in the developing cortex. PLoS One. 2010 Aug 25;5(8):e12376. doi: 10.1371/journal.pone.0012376.PMID:20811503
Nichols AJ, Olson EC. Reelin promotes neuronal orientation and dendritogenesis during preplate splitting. Cereb Cortex. 2010 Sep;20(9):2213-23. doi: 10.1093/cercor/bhp303. Epub 2010 Jan 11.PMID:20064940