During development, distinctive tissues form in the dorsal telencephalic midline (DTM) that separates the two cerebral cortices. Among these tissues are the cortical hem, which we recently identified as being a hippocampal organizer, and the choroid plexus, the source of cerebrospinal fluid (CSF). The choroid plexus is a well-known tissue with significant therapeutic potential, but its development is quite poorly understood. Moreover, failed DTM development is a central feature of holoprosencephaly (HPE), the most common congenital malformation of the human forebrain. The goal of this proposal is to elucidate the mechanisms and genetic network that govern DTM development, which will inform HPE pathogenesis and the generation of choroid plexus in culture for clinical applications. Previous studies have established central roles for the bone morphogenetic proteins (Bmps) in DTM development. For example, genetic ablation of the Bmp-producing roof plate in mice causes DTM induction deficits that can be rescued with exogenous Bmp4 alone. Nonetheless, fundamental questions about Bmp signaling and morphogenic activity remain unanswered. Genetic roof plate ablation also causes a dorsal form of HPE, which led to new discoveries about human HPE patients and a signaling network model of forebrain development that can explain how distinct human HPE phenotypes arise. However, within this network, insights into Bmp interactions are notably poor, including the identity of factors that inhibit the Bmp pathway to restrict DTM fates and position their borders. We previously used the roof plate ablation model to implicate Bmps in DTM induction in vivo. More recently, we demonstrated responses in cultured cortical neural precursor cells (NPCs) consistent with Bmp4 acting as a DTM morphogen, and identified the LIM homeodomain transcription factor Lhx2 as a cortical selector gene that suppresses cortical hem fate. In Preliminary Studies, we implicate fibroblast growth factor 8 (Fgf8) as a second DTM fate suppressor and describe enabling tools that include a new Bmp activity reporter mouse, a microfluidic culture system, and a mathematical model of DTM development. These findings and tools provide us with a unique opportunity, among vertebrate CNS model systems, to address fundamental questions in morphogen biology, developmental border formation, and Bmp activity regulation in addition to HPE pathogenesis and choroid plexus fate specification. In this proposal, we use validated in vivo, in vitro, microfluidic, and in silico tools to define the molecular mechanisms and genetic network that direct DTM development, focusing on Bmp activity and the factors that modulate it.

Public Health Relevance

The goal for this project is to better understand the network that governs development of the dorsal midline region in the telencephalon. The proposal is based on a signaling network model we developed that can explain holoprosencephaly, the most common congenital malformation of the human forebrain. The relevance of this project to public health derive mainly from the insights into this common birth defects, but also to the increasing number of psychiatric and neurologic diseases associated with neural stem cell defects, and to NSC and other stem cell strategies aimed at treating these brain disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Owens, David F
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University of California Irvine
Schools of Medicine
United States
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Barkho, Basam Z; Monuki, Edwin S (2015) Proliferation of cultured mouse choroid plexus epithelial cells. PLoS One 10:e0121738
Hong, Tian; Fung, Ernest S; Zhang, Lei et al. (2015) Semi-adaptive response and noise attenuation in bone morphogenetic protein signalling. J R Soc Interface 12:
Srinivasan, Shyam; Hu, Jia Sheng; Currle, D Spencer et al. (2014) A BMP-FGF morphogen toggle switch drives the ultrasensitive expression of multiple genes in the developing forebrain. PLoS Comput Biol 10:e1003463
Lehtinen, Maria K; Bjornsson, Christopher S; Dymecki, Susan M et al. (2013) The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci 33:17553-9
Watanabe, Momoko; Kang, Young-Jin; Davies, Lauren M et al. (2012) BMP4 sufficiency to induce choroid plexus epithelial fate from embryonic stem cell-derived neuroepithelial progenitors. J Neurosci 32:15934-45
Doan, Linda T; Javier, Anna L; Furr, Nicole M et al. (2012) A Bmp reporter with ultrasensitive characteristics reveals that high Bmp signaling is not required for cortical hem fate. PLoS One 7:e44009