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Franco Lab



My lab is currently studying two related developmental processes
involved in the formation of neural circuits in the cerebral cortex:
  1. Coordination between cell-fate specification and neurogenesis
    in neural stem cells
  2. The cellular and molecular mechanisms that control migration of newborn neurons and their integration into the cortical circuitry

Our immediate focus is on determining the molecular mechanisms by which fate-specification, neurogenesis and cell migration are temporally controlled and integrated to form layers of functionally related projection neurons in the cerebral cortex.

 




DwyerBrett (074) 2013.jpg


   Brett Dwyer, B.S., Professional Research Assistant

WinklerCaitlin (064) 2013.jpg





   Caitlin Winkler, B.S., Professional Research Assistant

 




 

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Trotter J, Lee GH, Kazdoba T, Crowell B, Domogauer J, Mahoney H, Franco SJ, Muller U, Weeber E, D'Arcangelo G. Dab1 is required for hippocampal synaptic plasticity and associative learning. J. Neurosci. 2013, in press.

Franco SJ, Muller U. Shaping our minds: stem and progenitor cell diversity in the mammalian neocortex. Neuron 2013 Jan 9;77(1):19-34.

Brunne B, Franco S, Bouche E, Herz J, Howell BW, Pahle J, Muller U, May P, Frotscher M, Bock HH. Role of the postnatal radial glial scaffold for the development of the dentate gyrus as revealed by reelin signaling mutant mice. Glia 2013 Aug;61(8):1347-63.

Gil-Sanz C, Franco SJ, Martinez-Garay I, Espinosa A, Harkins-Perry S, Muller U. Cajal-Retzius cells nstruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues. Neuron 2013 Aug 7;79(3):461-77.

Franco SJ, Gil-Sanz C, Martinez-Garay I, Espinosa A, Harkins-Perry SR, Ramos C, Muller U. Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 2012 Aug 10;337(6095):746-9.

Franco SJ, Muller U. Extracellular matrix functions during neuronal migration and lamination in the mammalian central nervous system. Dev Neurobiol. 2011 Nov;71(11):889-900.

Barros CS, Franco SJ, Muller U. Extracellular matrix: functions in the nervous system. Cold Spring Harb Perspect Biol, 2011 Jan 1;3(1):a005108.

Franco, SJ, Martinez-Garay I, Gil-Sanz C, Harkins-Perry SR, Muller U. Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex. Neuron. 2011 Feb 10;69(3):482-97.

Franco SJ, Muller U. Extracellular matrix functions during neuronal migration and lamination in the mammalian central nervous system. Dev Neurobiol. 2011 Nov;71(11):889-900.

Simonson WT, Franco SJ, Huttenlocker A. Talin1 regulates TCR-mediated LFA-1 function. J Immunol. 2006 Dec 1;77(11):7707-14.

Franco SJ, Senetar MA, Simonson WT, Huttenlocher A, McCann RO. The conserved C-terminal I/L WEQ module targets Talin1 to focal adhesions. Cell Motil Cytoskeleton. 2006 Sep;63(9):563-81.

Franco SJ, Huttenlocher A. Regulating cell migration: calpains make the cut. J Cell Sci, 2005 Sep 1:118(Pt 17):3829-38.

Franco SJ, Rodgers MA, Perrin BJ, Han J, Bennin DA, Critchley DR, Huttenlocher A. Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat Cell Biol. 2004 Oct;6(10):977-83.

Coordination between cell-fate specification and neurogenesis in neural stem cells.

Our previous studies led to a new model for how different classes of cortical projection neurons are specified from their progenitors (Franco, et. al., Science 2012; Franco and Mueller, Neuron 2013). Using genetic fate-mapping experiments in vivo, we showed that there are at least 2 distinct subtypes of radial glia progenitors that are fate-restricted to generate different functional classes of excitatory projection neurons. Importantly, this restriction is in place even before the progenitors begin making neurons, indicating a model in which some aspects of fate specification are initiated at the earliest stages of forebrain development from neural stem cells. These findings challenge the prevailing “common progenitor” hypothesis and raise a number of very intriguing new questions about how diversity among cortical cell types is achieved during embryonic development. One project in my lab involves the identification of the molecular programs that link fate specification to the timing of neurogenesis in these two progenitor subtypes. Another set of projects is aimed at studying progenitor diversification mechanisms in various other CNS cell types.
Migration of newborn neurons and their integration into the cortical circuitry.

One of the most prominent anatomical features of the neocortex is its laminar organization, in which neurons with similar properties are segregated into specific cell layers that allow connections to be made efficiently. Importantly, none of the cortical cell types are actually generated locally within the cerebral cortex proper, but are made in distant germinal zones from where they migrate into the cortex. Therefore, the precise organization of the cerebral cortex depends on coordinated cycles of cell-fate specification, neurogenesis and neuronal migration. One of the best-known signaling molecules required for neuronal migration and cortical layer formation is Reelin. Mutations in Reelin signaling cause severe cortical abnormalities in humans and mice, including lissencephaly and disorganized layers. Reelin is a secreted glycoprotein that binds to receptors on the surface of migrating neurons, thereby inducing phosphorylation of the cytoplasmic adaptor protein Dab1, which is essential for all known processes in the signaling pathway downstream of Reelin. Using precisely timed conditional knockout of Dab1 in migrating neurons in the cerebral cortex, we recently defined the cellular mechanism of Reelin function in cortical lamination and elucidated the molecular pathway downstream of Reelin signaling during neuronal migration (Franco, et al, Neuron 2010; Gil-Sanz, et al, Neuron 2013). In addition, we have recently identified several protein families that represent novel Dab1-binding partners in the developing and mature brain. Multiple projects in my lab are now aimed at determining the molecular and cellular mechanisms by which these novel Dab1-binding partners contribute to development and function of neural circuits in the central nervous system by regulating projection neuron migration and differentiation.