Developmental lineage of cell types in cortical dysplasia with balloon cells
1PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, USA, 2Netherlands Institute for Neuroscience, Amsterdam, The Netherlands, 3Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada and 4Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands
Correspondence to: Peter B. Crino, Department of Neurology, 3 West Gates Bldg, 3400 Spruce St, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA E-mail: peter.crino{at}uphs.upenn.edu
Focal cortical dysplasia type IIB with Ballon cells is a developmental malformation of the cerebral cortex highly associated with epilepsy. As a strategy to define the embryonic origin and neurochemical phenotype of cells in this disease, we probed specimens (n = 10) resected during epilepsy surgery with a panel of 13 antibodies recognizing proteins associated with (i) specific progenitor cell types including brain lipid binding protein (BLBP), collapsin response mediator protein 4 (CRMP4), Dlx1, Dlx2, GFAP
, MASH1, Otx1, Pax6, vimentin and phosphorylated vimentin and (ii) excitatory or inhibitory neurochemical phenotypes such as the vesicular glutamate transporters-1 and 2 (VGLUT-1, VGLUT-2), or the vesicular GABA transporter (VGAT). Balloon cells and large dysplastic neurons in all specimens expressed Otx1, phospho-vimentin, Pax6 and BLBP, proteins normally expressed by cells in the embryonic ventricular zone. A subpopulation of balloon cells expressed MASH-1 also expressed in the ventricular zone. Most balloon cells and dysplastic neurons were VGLUT2 immunoreactive, whereas none expressed Dlx1 or Dlx2, markers for inhibitory cells derived from the medial ganglionic eminence and few expressed VGAT, found in GABAergic interneurons. Otx1 mRNA expression and Dlx1 mRNA absence was confirmed by single cell RT-PCR. A subpopulation of balloon cells was labelled with CRMP4 and GFAP, markers specific for newly generated cells derived from the adult subventricular zone. Detection of Otx1, phospho-vimentin, Pax6 and BLBP expression but absence of Dlx1/Dlx2 expression suggests that balloon cells and dysplastic neurons derive from radial glial cells in the telencephalic ventricular zone and not the medial ganglionic eminence. VGLUT expression argues that dysplastic neurons may be glutamatergic. CRMP-4 and GFAP expression suggests that new cells may arrive in focal cortical dysplasia, perhaps deriving in part from the subventricular zone. These findings provide a developmental lineage model in which balloon cells and dysplastic neurons are derived from radial glial progenitor cells.
Key Words: cortical dysplasia; molecular genetics; development of brain; epileptology
Abbreviations: BC, balloon cell; BLBP, brain lipid binding protein; CRMP4, collapsin response mediator protein 4; DN, dysmorphic neuron; FCDIIB, Focal cortical dysplasia type IIB with balloon cells; MGE, medial ganglionic eminence; SVZ, subventricular zone; VGAT, vesicular GABA transporter; VGLUT 1 and VGLUT 2, vesicular glutamate transporters-1 and 2; VZ, telencephalic ventricular zone
Received April 2, 2007. Revised June 29, 2007. Accepted July 9, 2007.