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Title page for ETD etd-10262005-161737


Type of Document Dissertation
Author Von Stetina, Stephen Edward
Author's Email Address steve.vonstetina@vanderbilt.edu
URN etd-10262005-161737
Title Genomic strategies reveal a transcriptional cascade that controls synaptic specificity in Caenorhabditis elegans
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
David I. Greenstein Committee Chair
Christopher V. E. Wright Committee Member
David M. Miller, III Committee Member
Randy Blakely Committee Member
Richard O'Brien Committee Member
Keywords
  • genomics
  • developmental neurobiology
  • genetics
  • Caenorhabditis elegans -- Nervous system
  • Caenorhabditis elegans -- Genetics
Date of Defense 2005-09-06
Availability unrestricted
Abstract
Proper function of the brain requires that neurons adopt different morphologies and connections. In the nematode C. elegans, VA and VB motor neurons arise from a common precursor cell but adopt different morphologies and accept input from separate sets of command interneurons. In unc-4 mutants, VA motor neurons are miswired with VB-type inputs. We have proposed that miswiring results when VB genes are ectopically expressed in the VAs in unc-4 mutants. Previous work revealed that UNC-4 functions with the UNC-37/Groucho co-repressor protein to repress the VB-specific genes acr-5, del-1, glr-4. However, our genetic data rule out roles for these VB genes in synaptic choice. To identify the missing unc-4 target genes, a microarray-based strategy for profiling VA motor neurons was adopted.

A comparison of VA-specific transcripts isolated by mRNA-tagging from wildtype and unc-37 mutant animals revealed ~250 upregulated transcripts in unc-37 animals. One of these genes, ceh-12, is the C. elegans homolog of HB9, a homeodomain transcription factor with conserved roles in motor neuron fate in flies and vertebrates (Arber et al 1999, Broihier and Skeath 2002). In C. elegans, ceh-12::GFP is exclusively expressed in VB motor neurons in wildtype animals. In unc-4 and unc-37 mutants, ceh-12::GFP is also expressed in VA motor neurons as suggested by the microarray data. Thus, CEH-12 is a strong candidate for an UNC-4 target gene that regulates synaptic choice.

To test this idea, the unc-4 promoter was used to drive CEH-12 expression in wildype VA motor neurons. These animals exhibit an Unc-4 like backward movement defect, as expected for a model in which ectopic CEH-12 is sufficient to impose VB type inputs. In addition, we also showed that ceh-12 deletion mutants are partial suppressors of Unc-4 movement, thereby confirming that CEH-12 is also required for the Unc-4 miswiring defect. We conclude the VB-specific gene, ceh-12, is normally repressed in VA motor neurons to prevent the imposition of VB-type inputs. The incomplete suppression of unc-4, however, suggests that UNC-4 also controls other downstream target genes that function in parallel pathways to regulate synaptic choice.

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  01ChapterI.pdf 10.21 Mb 00:47:16 00:24:18 00:21:16 00:10:38 00:00:54
  02ChapterII.pdf 438.18 Kb 00:02:01 00:01:02 00:00:54 00:00:27 00:00:02
  03ChapterIII.pdf 28.75 Mb 02:13:07 01:08:27 00:59:54 00:29:57 00:02:33
  04ChapterIV.pdf 12.42 Mb 00:57:29 00:29:33 00:25:52 00:12:56 00:01:06
  05ChapterV.pdf 7.04 Mb 00:32:36 00:16:46 00:14:40 00:07:20 00:00:37
  06ChapterVI.pdf 1.55 Mb 00:07:11 00:03:41 00:03:14 00:01:37 00:00:08

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