Developmental defects in neuronal migration, maturation and connectivity are commonly found in human neurological diseases including epilepsy, schizophrenia and mental retardation. The acquisition of appropriate neuronal features during brain development is crucial for its function in adult life. However, the molecular mechanisms that regulate many aspects of brain development are poorly understood. The best characterized factor that determines the cytoarchitecture of cortical brain structures is reelin, the gene disrupted in the mutant reeler mouse, in the absence of the Reelin protein, many aspects of brain development are abnormal including neuronal migration, leading to the disruption of cellular layers, and dendrite development. Reelin is an extracellular protein produced in cortical marginal layers and subject to proteotytic cleavage. It was previously demonstrated that the Reelin signal that controls cortical layer formation is mediated by two cell surface receptors, the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), and by the intracellular adapter protein Disabled1 (Dab1). In addition, Reelin possesses a protease activity that could also be important for brain development. In superficial Reelin-rich layers, most principal neurons terminate their migration and develop an initial dendritic arborization. However, it is unclear whether Reelin directly regulates dendrite growth and little is known about the cellular events that mediate its function. We propose that Reelin functions by inducing cytoskeletal changes that enable correct neuronal positioning during embryonic development and dendrite maturation in the postnatal brain. In this proposal, we will test the hypothesis that Reelin directly regulates the growth of hippocampal pyramidal cell dendrites and elucidate the molecular events that mediate this function. A combination of biochemical, genetic, cell biology and molecular approaches will be taken to test our hypothesis. Recombinant Reelin will be purified and characterized biochemically, hippocampal dendrite development will be studied in vivo and in vitro using mutant and transgenic mice, and novel downstream targets of Reelin will be identified by genetic screens. Our studies will lead to a better understanding of Reelin function in normal brain development. Furthermore, our findings may have significant implications for cognitive disorders associated with Reelin deficiency.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Leblanc, Gabrielle G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Sunnen, C Nicole; Brewster, Amy L; Lugo, Joaquin N et al. (2011) Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia 52:2065-75
Yabut, Odessa; Domogauer, Jason; D'Arcangelo, Gabriella (2010) Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. J Neurosci 30:4004-14
Zhang, Guangcheng; Assadi, Amir H; Roceri, Mila et al. (2009) Differential interaction of the Pafah1b alpha subunits with the Reelin transducer Dab1. Brain Res 1267:1-8
Ljungberg, M Cecilia; Sunnen, C Nicole; Lugo, Joaquin N et al. (2009) Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2:389-98
Niu, Sanyong; Yabut, Odessa; D'Arcangelo, Gabriella (2008) The Reelin signaling pathway promotes dendritic spine development in hippocampal neurons. J Neurosci 28:10339-48
Assadi, Amir H; Zhang, Guangcheng; McNeil, Robert et al. (2008) Pafah1b2 mutations suppress the development of hydrocephalus in compound Pafah1b1;Reln and Pafah1b1;Dab1 mutant mice. Neurosci Lett 439:100-5
Zhang, Guangcheng; Assadi, Amir H; McNeil, Robert S et al. (2007) The Pafah1b complex interacts with the reelin receptor VLDLR. PLoS One 2:e252
Yabut, Odessa; Renfro, Amy; Niu, Sanyong et al. (2007) Abnormal laminar position and dendrite development of interneurons in the reeler forebrain. Brain Res 1140:75-83
D'Arcangelo, Gabriella (2006) Reelin mouse mutants as models of cortical development disorders. Epilepsy Behav 8:81-90
Panteri, Roger; Paiardini, Alessandro; Keller, Flavio (2006) A 3D model of Reelin subrepeat regions predicts Reelin binding to carbohydrates. Brain Res 1116:222-30

Showing the most recent 10 out of 12 publications