Nicholas Gaiano, Ph.D. Associate Professor of Neurology, Neuroscience, and Oncology Johns Hopkins University School of Medicine 733 N. Broadway, Suite 711 Baltimore, MD 21205 Phone: (443)-287-4866 (office); x7-5606 (lab) Fax: (443)-287-4868 Email: gaiano@jhmi.edu Neuroscience webpage  (Requires Adobe® Acrobat® Reader® to view.)

Research Summary

Our primary goal is to understanding the molecular regulation of neural stem and progenitor cells in the telencephalon, the embryonic structure that gives rise to the cerebral cortex, hippocampus, amygdala, and basal ganglia. By understanding how neural stem cells are regulating, both in terms of proliferation and the generation of neurons and glia, we will gain insight relevant both to the etiology and treatment of brain cancer, and also to the development of cell replacement strategies to treat the damaged or degenerating nervous system.

We have focused on the Notch signaling pathway, which is of fundamental importance to many processes during development and in the adult. With respect to the developing nervous system, Notch signaling is thought to maintain a stem cell/progenitor state and to inhibit neuronal differentiation. In addition, Notch has been shown to promote radial glial progenitor character during development and astrocyte fate postnatally. Much remains to be understood, on both molecular and cellular levels, about Notch function in neural stem and progenitor cells. The central project in our group continues to address these issues, and we have begun to diversify our interests into related areas.

Ongoing projects in the lab include:

Notch signaling in embryonic neural stem/progenitor cells. We have found that the Notch signaling pathway is differentially utilized in neural stem cells (NSCs) and intermediate neural progenitors (INPs). In NSCs, Notch signals through the canonical effector CBF1 (also called RBP-J and CSL), while in neuroblasts this signaling cascade is attenuated and/or redirected to non-canonical targets. We use our transgenic Notch reporter (TNR) mouse line, which expresses EGFP in cells with Notch/CBF1 activation, to separate these populations prospectively for study. Ongoing efforts are designed to identify the molecular mechanisms through which Notch signaling is differentially regulated in NSCs and INPs, and how these cell types differ on a molecular level at large. Of particular interest, we are examining the role of the transcriptional regulator Zbtb7a/LRF/Pokemon, which has been shown to antagonize Notch signaling during cell fate specification in the immune system.

NF-kB signaling in telencephalic development. Increasing evidence in the literature suggests that the Notch and NF-kB pathways may interact. With this in mind, we are examining the role of NF-kB signaling during neural stem/progenitor cell regulation in the embryonic forebrain. NF-kB has been heavily studied in the immune system and many tools are available to characterize and manipulate this pathway. We are taking both loss-of-function and gain-of-function approaches to determine the role of NF-kB in telencephalic stem/progenitor cells, and the extent to which NF-kB and Notch interact in this context.

Notch3 and tumor formation. We have found that an activated form of Notch3 can promote tumor formation in mice. Specifically, we have found that Notch3 activation leads to the formation of choroid plexus tumors (CPTs) and also to invasive ocular tumors. We are characterizing the origin and progression of the ocular tumors, which appear to be derived from both neural and non-neural cell types, and are akin to astrocytomas and ocular melanomas, respectively. In addition, was have found that unlike Notch3, activated Notch1 does not cause CPTs or ocular tumors. We are interested in identifying the molecular differences between Notch3 and Notch1 that make the former, but not the latter, tumorigenic in our system.

Notch activation in neurons. We are investigating a role for a Notch signaling in mature neurons. Prior work has suggested that Notch can influence the development of axons and dendrites, and may play a role during learning and memory. We have found that Notch signaling is activated in neurons in response to neuronal activity, and that such activation is dependent upon the neuronal plasticity gene Arc/Arg3.1. Ongoing efforts are designed to determine both how Notch is activated in neurons in an activity-dependent manner, and how Notch activation feeds back to alter neuronal function.

Our work is supported by grants from the NINDS (RO1 NS046731), NARSAD, the Simons Foundation, the James S. McDonnell Fund, and the Maryland Stem Cell Research Fund. Previous support has been provided by the Burroughs Wellcome Fund, the Sidney Kimmel Foundation for Cancer Research, and the NIMH (R21 MH073006)

Lab Members

Watch a movie of a student being mentored in the Gaiano lab [25.9Mb]

| Gaiano lab, 2007
Louis Dang and Nick Gaiano ... hard at work! former MSTP/Neuroscience Graduate Student ldang2@jhmi.edu
Lavinia Alberi, Ph.D. Postdoctoral Fellow lalberi@jhmi.edu	Melody Cheng BCMB Graduate Student melody@jhmi.edu
Tarran Pierfelice CMM Graduate Student tpierfe1@jhmi.edu	Karisa Schreck MSTP/Neuroscience Graduate Student ksolt1@jhmi.edu
Amalia Londono Undergraduate Student alondon7@jhu.edu	Kristina Shambry Research Technician shambryk@yahoo.com

Selected Publications

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