The long-term objective of this proposal is to contribute to the understanding of the initial development of the cerebral cortex. Specifically, we propose to study the role of human Cajal-Retzius (C-R) cells and layer I during early development. The overriding hypothesis to be tested is that the C-R cells are a diverse population of cells and that species- related differences in this diversity accounts for the fate of these cells during development. Cajal-Retzius cells are the main type of cell in the initial layer I (the preplate). By secreting the glycoprotein, reelin, C-R cells have been postulated to control the inside-out migration of cortical neurons and thus to play a fundamental morphogenic role in corticogenesis. The disruption of this process has been implicated in various neurodevelopmental disorders resulting in mental retardation, ectopias and epilepsy. In order to understand and ultimately prevent these pediatric disorders, there is a need to gain an appreciation of the mechanisms underlying normal brain development. Recent studies employing new markers of early cortical neurons reveal a cellular composition of the human preplate that is much more complex than the prevailing classical model. In this application, we propose 3 specific aims to address some of the most controversial and pressing issues related to C-R cells in human cortical development. We would like to know the answers to the following questions: (1) Do all C-R cells belong to a single unique class of cells or should they be classified instead into different subtypes on the basis of their antigenic phenotype, survival rate and transmitter receptor properties? (2) Are C-R cells generated at different times and from different places? (3) How do species- specific differences relate to functional properties, the survival and possible new roles of C-R cells in humans? Having available to us a well-characterized collection of human brains that spans the intrauterine period of development, we are in a uniquely favorable position to answer these questions. Normal development of the cerebral cortex is essential for proper functioning of the adult central nervous system. Data generated through this research will advance our understanding of normal brain development, and point to possible mechanisms that contribute to congenital brain malformations. In addition, our findings will establish a prerequisite set of baseline data for proper diagnosis and treatment of pediatric disorders of the CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041489-02
Application #
6540430
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Leblanc, Gabrielle G
Project Start
2001-05-15
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$295,282
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Memi, Fani; Zecevic, Nada; Radonji?, Nevena (2018) Multiple roles of Sonic Hedgehog in the developing human cortex are suggested by its widespread distribution. Brain Struct Funct 223:2361-2375
Ortega, J Alberto; Sirois, Carissa L; Memi, Fani et al. (2017) Oxygen Levels Regulate the Development of Human Cortical Radial Glia Cells. Cereb Cortex 27:3736-3751
Radonji?, Nevena V; Memi, Fani; Ortega, Juan Alberto et al. (2016) The Role of Sonic Hedgehog in the Specification of Human Cortical Progenitors In Vitro. Cereb Cortex 26:131-43
Selemon, L D; Zecevic, N (2015) Schizophrenia: a tale of two critical periods for prefrontal cortical development. Transl Psychiatry 5:e623
Radonji?, Nevena V; Ayoub, Albert E; Memi, Fani et al. (2014) Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche. Cell Rep 9:2139-51
Malik, Sabrina; Vinukonda, Govindaiah; Vose, Linnea R et al. (2013) Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth. J Neurosci 33:411-23
Reinchisi, Gisela; Limaye, Pallavi V; Singh, Mandakini B et al. (2013) Neurogenic potential of hESC-derived human radial glia is amplified by human fetal cells. Stem Cell Res 11:587-600
Reinchisi, Gisela; Ijichi, Kumiko; Glidden, Nicole et al. (2012) COUP-TFII expressing interneurons in human fetal forebrain. Cereb Cortex 22:2820-30
Mo, Zhicheng; Milivojevic, Verica; Zecevic, Nada (2012) Enforced Pax6 expression rescues alcohol-induced defects of neuronal differentiation in cultures of human cortical progenitor cells. Alcohol Clin Exp Res 36:1374-84
Jakovcevski, Igor; Mayer, Nicole; Zecevic, Nada (2011) Multiple origins of human neocortical interneurons are supported by distinct expression of transcription factors. Cereb Cortex 21:1771-82

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