Overview

The main focus of the laboratory is to understand the molecular mechanisms that generate the astounding diversity of cell types in a nervous system. Using the C.elegans model system, we have revealed a core regulatory logic for how terminal neuronal identity is controlled in several different neuron types [1-6]. We have demonstrated that these regulatory mechanisms are conserved in chordates [4, 5]. These insights have allowed us to reprogram the identity of heterologous cell types to that of specific neuron types [7, 8]. Venturing into a little explored area of neuronal diversification, we have developed a novel paradigm to study asymmetry across the left/right axis [9, 10], by far the least understood axis in any nervous system, and identified a complex gene regulatory network that differentially controls terminal neuron identity across this axis [11-24].

Aside from our main focus on neuronal development, we have also studied the molecular machinery with which the nervous system responds to the environment (i) to modulate behavior [10, 25-27] and (ii) to ensure that it maintains its functional and structural integrity [28-31].

Employing new technologies that we developed [32-35], we will continue to exploit the simplicity and experimental amenability of the worm to achieve a comprehensive understanding of the genetic programs that control the development of the C.elegans nervous system and we will continue to extend these insights to vertebrates.

More details about our research are available here:
Gene regulatory programs that build a nervous system

Left/Right asymmetric terminal differentiation programs in the nervous system

Plasticity & Maintenance: How the nervous system interacts with its environment

Conservation and evolution of neuronal gene expression programs

Methods

Bibliography:

1.         Hobert, O., Regulatory logic of neuronal diversity: terminal selector genes and selector motifs. Proc Natl Acad Sci U S A, 2008. 105(51): p. 20067-71.

2.         Wenick, A.S. and O. Hobert, Genomic cis-Regulatory Architecture and trans-Acting Regulators of a Single Interneuron-Specific Gene Battery in C. elegans. Dev Cell, 2004. 6(6): p. 757-70.

3.         Etchberger, J.F., et al., The molecular signature and cis-regulatory architecture of a C. elegans gustatory neuron. Genes Dev, 2007. 21(13): p. 1653-74.

4.         Flames, N. and O. Hobert, Gene regulatory logic of dopamine neuron differentiation. Nature, 2009. 458(7240): p. 885-9.

5.         Kratsios, P., et al., Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nat Neurosci, 2011. 15(2): p. 205-14.

6.         Hobert, O., I. Carrera, and N. Stefanakis, The molecular and gene regulatory signature of a neuron. Trends Neurosci, 2010. 33(10): p. 435-45.

7.         Tursun, B., et al., Direct conversion of C. elegans germ cells into specific neuron types. Science, 2011. 331(6015): p. 304-8.

8.         Patel, T., et al., Removal of Polycomb Repressive Complex 2 Makes C. elegans Germ Cells Susceptible to Direct Conversion into Specific Somatic Cell Types. Cell Rep, 2012. 2(5): p. 1178-86.

9.         Ortiz, C.O., et al., Searching for neuronal left/right asymmetry: genomewide analysis of nematode receptor-type guanylyl cyclases. Genetics, 2006. 173(1): p. 131-49.

10.      Ortiz, C.O., et al., Lateralized gustatory behavior of C. elegans is controlled by specific receptor-type guanylyl cyclases. Curr Biol, 2009. 19(12): p. 996-1004.

11.      Didiano, D., et al., Neuron-type specific regulation of a 3′UTR through redundant and combinatorially acting cis-regulatory elements. RNA, 2010. 16(2): p. 349-63.

12.      Etchberger, J.F., et al., Cis-regulatory mechanisms of left/right asymmetric neuron-subtype specification in C. elegans. Development, 2009. 136(1): p. 147-60.

13.      Poole, R.J., et al., A Genome-Wide RNAi Screen for Factors Involved in Neuronal Specification in Caenorhabditis elegans. PLoS Genet, 2011. 7(6): p. e1002109.

14.      Poole, R.J. and O. Hobert, Early embryonic programming of neuronal left/right asymmetry in C. elegans. Curr Biol, 2006. 16(23): p. 2279-92.

15.      Sarin, S., et al., The C. elegans Tailless/TLX transcription factor nhr-67 controls neuronal identity and left/right asymmetric fate diversification. Development, 2009. 136(17): p. 2933-44.

16.      Sarin, S., et al., Genetic Screens for Caenorhabditis elegans Mutants Defective in Left/Right Asymmetric Neuronal Fate Specification. Genetics, 2007. 176(4): p. 2109-30.

17.      O’Meara, M.M., et al., Cis-regulatory Mutations in the Caenorhabditis elegans Homeobox Gene Locus cog-1 Affect Neuronal Development. Genetics, 2009. 181: p. 1679–1686.

18.      O’Meara, M.M., F. Zhang, and O. Hobert, Maintenance of neuronal laterality in Caenorhabditis elegans through MYST histone acetyltransferase complex components LSY-12, LSY-13 and LIN-49. Genetics, 2010. 186(4): p. 1497-502.

19.      Zhang, F., M.M. O’Meara, and O. Hobert, A left/right asymmetric neuronal differentiation program is controlled by the Caenorhabditis elegans lsy-27 zinc-finger transcription factor. Genetics, 2011. 188(3): p. 753-9.

20.      Flowers, E.B., et al., The Groucho ortholog UNC-37interacts with the short Groucho-like protein LSY-22 to control developmental decisions in C. elegans. Development, 2010. 137: p. 1799-1805.

21.      Johnston, R.J., Jr., et al., MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. Proc Natl Acad Sci U S A, 2005. 102(35): p. 12449-54.

22.      Johnston, R.J., Jr., et al., An unusual Zn-finger/FH2 domain protein controls a left/right asymmetric neuronal fate decision in C. elegans. Development, 2006. 133(17): p. 3317-28.

23.      Johnston, R.J., Jr. and O. Hobert, A novel C. elegans zinc finger transcription factor, lsy-2, required for the cell type-specific expression of the lsy-6 microRNA. Development, 2005. 132(24): p. 5451-60.

24.      Cochella, L. and O. Hobert, Embryonic Priming of a miRNA Locus Predetermines Postmitotic Neuronal Left/Right Asymmetry in C. elegans. Cell, 2012. 151(6): p. 1229-42.

25.      Pocock, R. and O. Hobert, Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans. Nat Neurosci, 2008. 11(8): p. 894-900.

26.      Pocock, R. and O. Hobert, Hypoxia activates a latent circuit for processing gustatory information in C. elegans. Nat Neurosci, 2010. 13(5): p. 610-4.

27.      Remy, J.J. and O. Hobert, An interneuronal chemoreceptor required for olfactory imprinting in C. elegans. Science, 2005. 309(5735): p. 787-90.

28.      Benard, C. and O. Hobert, The secreted Ig domain proteins ZIG-5 and ZIG-8 genetically interact with L1CAM/SAX-7 to maintain neuronal soma position. submitted, 2011.

29.      Benard, C., et al., The small, secreted immunoglobulin protein ZIG-3 maintains axon position in Caenorhabditis elegans. Genetics, 2009. 183(3): p. 917-27.

30.      Pocock, R., et al., Functional dissection of the C. elegans cell adhesion molecule SAX-7, a homologue of human L1. Mol Cell Neurosci, 2008. 37(1): p. 56-68.

31.      Benard, C.Y., et al., DIG-1, a novel giant protein, non-autonomously mediates maintenance of nervous system architecture. Development, 2006. 133(17): p. 3329-40.

32.      Bigelow, H., et al., MAQGene: software to facilitate C. elegans mutant genome sequence analysis. Nat Methods, 2009. 6(8): p. 549.

33.      Doitsidou, M., et al., C. elegans Mutant Identification with a One-Step Whole-Genome-Sequencing and SNP Mapping Strategy. PLoS ONE, 2010. 5(11): p. e15435.

34.      Doitsidou, M., et al., Automated screening for mutants affecting dopaminergic-neuron specification in C. elegans. Nat Methods, 2008. 5(10): p. 869-72.

35.      Minevich, G., et al., CloudMap: A Cloud-Based Pipeline for Analysis of Mutant Genome Sequences. Genetics, 2012. 192(4): p. 1249-69.