We study the relatively simple nervous system of the fruitfly (Drosophila melanogaster) to to understand the molecular, genetic and cellular mechanisms involved in neuron generation during development.
Nervous systems consist of a huge number and variety of interconnected neuronal cells. These cells must be generated during embryonic development, they must be assigned their various identities, and they must differentiate according to these identities to give functionally distinct working neurons. These are problems of neurogenesis.
To address such questions, we study the relatively simple sensory nervous system of a model organism - the fruitfly (Drosophila melanogaster), which is composed of a variety of sensory neurons innervating sense organs.
Through this model, we hope to uncover the molecular and cellular rules that govern how neurons are made. Importantly, the molecules and mechanisms turn out to be highly conserved between Drosophila and humans.
Ultimately, understanding neurogenesis requires knowing how the expression of a large number of genes is choreographed in time and space. One focus for our study is the proneural bHLH transcription factors. Proneural factors trigger cells to become neurons by activating the expression of neural genes.
Whilst first discovered and extensively characterized in Drosophila, these factors govern neuron generation in all metazoans. We discovered several proneural factors in Drosophila, notably Atonal, which is required for stretch receptors, auditory neurons and photoreceptors, and Amos, which is required for most olfactory neurons (Goulding et al., 2000; zur Lage et al., 2003). One strand of our current work is to determine how proneural factors interact with DNA to regulate genes at the molecular level (Powell et al., 2004, 2008).
Another major research strand is to identify the neural genes that proneural factors like Atonal regulate. We recently carried out transcriptome analysis on Atonal-dependent stretch receptor neurons to determine this (Cachero et al., 2011).
One of our major goals is to understand how proneural factor activity leads ultimately to the differentiation of specialized sensory neurons. Our transcriptome analysis revealed that Atonal activates a series of other transcription factors that in turn regulate genes required for the construction of specialized parts of the sensory neurons.
We found recently that two of these factors are intimately involved in construction of the sensory cilium (Cachero et al., 2011). This structure is the site of sensory reception and transduction. One of these factors, Rfx, is a highly conserved regulator of ciliary genes in general. The other, Fd3F, is a novel Fox factor that regulates genes required for specialization of the neuronal sensory cilium to tailor it for its auditory and stretch reception role.
Increasingly, we are turning to computational analyses to understand the large amounts of data generated by these studies, and also to generate computer models of gene regulation during neurogenesis. This entails development of new computational tools in a close ongoing collaboration with members of the School of Informatics (Simpson et al., 2010; Gallone et al., 2011).
As mentioned above, our work on proneural factors has led somewhat unexpectedly into the regulation of genes required for cilium formation and function. In fact the biology of cilia is an important topic in its own right. Cilia are almost ubiquitous organelles in humans, being required for cellular sensing during development and physiology.
This is true not only of sensory cells (such as rods and cones in the retina), but also of cells in a variety of organs, such as the kidney and pancreas. Other cilia are motile and move fluid in lungs, CNS, and female reproductive tract. Increasingly, human diseases are being attributed to cilia malformation or malfunction (e.g. ciliopathies, polycystic kidney disease).
The genes required for cilium construction and function are highly conserved. Identifying and analysing genes that are activated by Atonal, Rfx and Fd3F gives us a significant inroad into discovering new ciliary genes that may be important in humans.
Unlike vertebrates, in Drosophila cilia are confined to sensory neurons, and so defects in ciliary genes result in flies with a highly characteristic sensory deficit that is readily accessible to analysis.
To identify ciliary genes we are using a combination of functional genomics, computational modeling of protein-protein interactions, and genetic screening for uncoordinated flies.
We are characterizing several exciting new genes, including dilatory, which encodes a protein that localises to the base of the sensory cilium where it regulates transport into the cilium (Ma and Jarman, 2011).
Powell, L.M., Chen, A., Huang, Y.C., Want, P.Y. Kemp, S.E., and Jarman, A.P. 2012. The SUMO pathway promotes bHLH proneural factor activity via a direct effect on the zinc finger protein, Senseless. Mol. Cell. Biol. In press.
Newton, F.G., zur Lage, P.I., Karak, S., Moore,D.J., Göpfert, M.C., and Jarman, A.P. 2012. Forkhead transcription factor Fd3F cooperates with Rfx to regulate a gene expression program for mechanosensory cilia specialization. Dev. Cell, 22: 1221-1233.
zur Lage, P.I., Simpson, T.I., Jarman, A.P. 2011. Linking specification to differentiation: from proneural genes to the regulation of ciliogenesis. Fly, in press.
Gallone, G., Simpson, T.I., Armstrong, J.D., and Jarman, A.P. 2011. Bio::Homology:InterologWalk — a Perl module to build putative protein-protein interaction networks through interolog mapping. BMC Bioinformatics, 12: 289. Highly accessed.
Ma, L., and Jarman, A.P. 2011. Dilatory is a Drosophila protein related to AZI1/CEP131 that is located at the ciliary base and required for cilium formation. J. Cell Sci. 123: e1504.
Cachero, S., Simpson, T.I., zur Lage, P.I., Ma, L., Newton, F.G., Holohan, E.E., Armstrong, J.D, and Jarman, A.P. 2011. The gene regulatory cascade linking proneural specification with differentiation in Drosophila sensory neurons. PLoS Biology 9(1): e1000568.
Simpson, T.I., Armstrong, J.D., and Jarman, A.P. 2010. Merged consensus clustering to assess and improve class discovery with microarray data. BMC Bioinformatics 11:590. Highly accessed.
zur Lage, P.I. and Jarman, A.P. 2010. The function and regulation of the bHLH gene, cato, in Drosophila neurogenesis. BMC Developmental Biology 10: 34.
Powell, L.M. and Jarman, A.P. 2008. Context dependence of proneural bHLH proteins. Curr. Op. Genet. Dev. 18: 411-417.
Powell, L.M., Deaton, A.M., Wear, M.A. and Jarman, A.P. 2008. The specificity of Atonal and Scute bHLH factors: analysis of cognate E box binding sites and the influence of Senseless. Genes to Cells. 13, 915-927.
Maung, S.M.T., Ahmed, I., and Jarman, A.P. 2007. On the neural specificity of the Atonal-like proteins, Amos and Atonal. Mech Dev. 124: 647-656.
zur Lage, P.I., Powell, L.M., Prentice, D.R.A., McLaughlin, P., and Jarman, A.P. 2004. EGF receptor signalling triggers recruitment of Drosophila sense organ precursors by stimulating proneural gene autoregulation. Developmental Cell 5: 687-696.
Rawlins, E.L., Lovegrove, B., and Jarman, A.P. 2003. Echinoid facilitates Notch pathway signalling during Drosophila neurogenesis through functional interaction with Delta. Development 130: 6475-6484.
Jarman, A.P. 2002. Studies of mechanosensation in Drosophila. Hum. Mol. Genet. 11: 1215-1218.
Goulding, S.E., zur Lage, P., and Jarman, A.P. 2000. amos, a proneural gene required for olfactory sense organs that is regulated by lozenge. Neuron 25: 69-78.
zur Lage, P., and Jarman, A.P. 1999. Antagonism of EGFR and Notch signalling in the reiterative recruitment of adult Drosophila chordotonal sense organ precursors. Development 126: 3149-3157.