A wealth of data suggest that aberrations in Notch signaling in humans results in a host of development brain disorders, such as CADASIL disease. This grant examines the functions of Notch signaling during neurogenesis in the telencephalon, using a combined gain of function/loss of function approach. We hypothesize that Notch function can be divided into distinct early and late roles. We believe that the function of Notch signaling during early neurogenesis is to maintain progenitors in an undifferentiated state. By contrast, in late telencephalic development, we believe Notch signaling functions to determine neuronal versus glial identity. To test the first part of this model, we will examine the consequences of perturbing Notch signaling in the early embryo by systematically removing the different Notch receptors or by conditional ablation of RBP, an obligate downstream effector required for Notch signaling. To look at the later roles of Notch signaling, we will use both transgenic and virally-mediated methods for modulating Notch signaling both globally and mosiacally within the telencephalon. We will thus directly test in late neurogenesis whether changes in Notch signaling result in progenitors being biased to a neuronal or glial identity. Furthermore, to examine whether Notch function during this period of telencephalic development is acting in an instructive or permissive manner, we have designed an approach to transiently activate Notch signaling, to see if this abrogates telencephalic progenitors' ability to adopt a neuronal identity when shifted to in vivo or in vitro to neurogenic environments. These studies will provide an accurate accounting of the function of Notch signaling both temporally and spatially within the developing telencephalon. By determining the consequences of Notch signaling in different developmental consequences, this study will determine whether qualitative as well as quantitative changes in the requirement for Notch signaling occur at various time points of development. Furthermore, given recent evidence that Notch function plays a central role in maintaining CNS stem cells and acts in determining cell fates, better understanding the role of this pathway in normal development will provide clues as to how patterning and neurogenesis are coordinated and open the way to the development of rational cell replacement therapies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
Zip Code
Tuncdemir, Sebnem N; Wamsley, Brie; Stam, Floor J et al. (2016) Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits. Neuron 89:521-35
Cassataro, Daniela; Bergfeldt, Daniella; Malekian, Cariz et al. (2014) Reverse pharmacogenetic modulation of the nucleus accumbens reduces ethanol consumption in a limited access paradigm. Neuropsychopharmacology 39:283-90
Fu, Yuhong; Tvrdik, Petr; Makki, Nadja et al. (2013) The interfascicular trigeminal nucleus: a precerebellar nucleus in the mouse defined by retrograde neuronal tracing and genetic fate mapping. J Comp Neurol 521:697-708
Patel, Jyoti C; Rossignol, Elsa; Rice, Margaret E et al. (2012) Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits. Nat Commun 3:1172
Rudy, Bernardo; Fishell, Gordon; Lee, SooHyun et al. (2011) Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol 71:45-61
Fishell, Gord; Rudy, Bernardo (2011) Mechanisms of inhibition within the telencephalon: ""where the wild things are"". Annu Rev Neurosci 34:535-67
Machold, R; Klein, C; Fishell, G (2011) Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip. Gene Expr Patterns 11:349-59
Sousa, Vitor H; Fishell, Gord (2010) Sonic hedgehog functions through dynamic changes in temporal competence in the developing forebrain. Curr Opin Genet Dev 20:391-9
Sousa, Vitor H; Miyoshi, Goichi; Hjerling-Leffler, Jens et al. (2009) Characterization of Nkx6-2-derived neocortical interneuron lineages. Cereb Cortex 19 Suppl 1:i1-10
Batista-Brito, Renata; Rossignol, Elsa; Hjerling-Leffler, Jens et al. (2009) The cell-intrinsic requirement of Sox6 for cortical interneuron development. Neuron 63:466-81

Showing the most recent 10 out of 20 publications