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SUMMARY:Functional Genomics: Phenotypic screening of large gene sets to id
 entify novel genes that regulate axon growth and branching. - Vance Lemmon
  Miami Project to Cure Paralysis
DTSTART:20090331T135500Z
DTEND:20090331T144000Z
UID:TALK17643@talks.cam.ac.uk
CONTACT:Anna Di Pietro
DESCRIPTION:Injuries to the spinal cord and brain often lead to irreversib
 le damage. Central Nervous System (CNS) neurons have difficulty regenerati
 ng axons\, due to both environmental and intrinsic factors.  To better und
 erstand the intrinsic factors limiting the regenerative ability of CNS neu
 rons\, we conducted three high content screens (HCS) in primary neurons.  
 We over-expressed genes in the neurons and then analyzed the changes in ne
 urite growth. Using automated image acquisition and analysis\, we tested 2
 0-90 genes per day\, with multiple morphological parameters (e.g. neurite 
 number\, length\, branching\, etc.) measured from 100\,000 to 300\,000 neu
 rons in a single experiment. \nFor the first screen we compared patterns o
 f gene expression of CNS neurons with Peripheral Nervous System (PNS) neur
 ons\, which have a greater intrinsic capacity for regeneration. This compa
 rison yielded 1300 candidate genes for functional testing.  For the second
  screen we compared gene expression in mature corticospinal tract neurons 
 to their embryonic counterparts\, which also display a high intrinsic capa
 city for regeneration\, and generated a list of about 800 genes.  The thir
 d screen examined over 600 kinases\, phosphatases and their related enzyme
 s and adaptors.\n  	We identified a number of genes known to regulate axon
  growth\, including ERK2\, GSK3b\, EphA7\, FGFR1\, PI3K\, PKC and CAMK1a. 
 This validates the effectiveness of our screens.  We have also identified 
 a number of novel genes\, not previously associated with neurite growth.  
 We used bioinformatics approaches to cluster genes with different aspects 
 of neurite growth\, and found that that there is a poor correlation betwee
 n genes associated with neurite extension and those involved in formation 
 of neurites emerging from the cell body.  By testing the genes on permissi
 ve substrates such as laminin\, and inhibitory substrates such as chondroi
 tin sulfate proteoglycans (CSPG)\, we identified specific cDNAs that incre
 ase growth in primary neuron cultures only on the CSPGs\, and others that 
 decrease growth only on laminin.\nOur data show that phenotypic screening 
 provides a robust approach for identifying novel genes and signaling pathw
 ays that function in axon growth\, and will lead to a greater understandin
 g of the mechanisms needed for achieving neuron regeneration after injury 
 in vivo. \n
LOCATION:Cripps Court\, Magdalene College
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