We wish to understand the molecular, genetic and cellular mechanisms underlying sensory neuron generation and function, particularly concentrating on auditory receptors and other mechanoreceptors.
We study the relatively simple sensory nervous system of the fruit fly (Drosophila melanogaster) to address such questions as:
(1) How are sensory neurons generated during development (i.e. neurogenesis). This entails understanding the transcriptional regulation of the large batteries of genes required for neurogenesis.
(2) How is cellular differentiation regulated to give specialised sensory neuron subtypes (e.g. mechanosensory, auditory). This entails understanding both the transcriptional regulation of the specialised genes involved (e.g. for the mechanosensory apparatus) and the cell biological pathways underlying differentiation (e.g. chaperone pathways for macromolecular assembly).
Through this model system, 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, which has led us into two avenues of research directly relevant to human disease.
Understanding neurogenesis requires knowing how the expression of a large group of neural genes is choreographed in time and space. The generation of sensory neurons is triggered by ‘master regulators’: proneural bHLH transcription factors.
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). It turns out that the atonal gene is highly conserved and its human equivalent (Atoh1) regulates the formation of auditory sensory cells of the inner ear (see below).
To understand how Atonal transcription factor regulates the differentiation of specialized mechanosensory neurons, a major theme is to identify and characterise its target genes. We carried out transcriptome analysis of the time course of expression changes in developing Atonal-dependent auditory receptor neurons.
This analysis revealed that Atonal regulates a series of other transcription factors (Rfx and Fd3F) that in turn regulate the genes required for the construction of specialized parts of these mechanosensory neurons (Cachero et al., 2011).
A major feature of Drosophila auditory neurons is that they have a terminal sensory cilium, which is the site of sensory reception and transduction. Mechanical stimulation of the cilium leads to opening of mechanosensory ion channels, ultimately causing the neurons to fire.
We found recently that all the genes required to construct the cilium and its associated mechanotransduction machinery are regulated directly by Rfx and Fd3F working together. Rfx is a highly conserved regulator of ciliary genes in general. Fd3F is a novel Fox family factor that regulates genes required for specialization of the sensory cilium to configure it for its auditory and stretch reception role (Newton et al., 2012).
Recently, in collaboration with Joerg Albert (Ear Institute, UCL), we have extended our investigation of analysis of auditory neuron gene regulation to asking how transcriptional regulation is achieved in the mature auditory neurons to maintain their function over the life course of the fly.
Cilia are almost ubiquitous cellular organelles in humans, being required for cellular sensing during development and physiology. Increasingly, human diseases (ciliopathies) are being attributed to cilia malformation or malfunction. Some cilia are motile due to the presence of dynein motor complexes within them.
Motile cilia are required for mucociliary clearance, embryonic determination of left-right asymmetry, and male and female fertility. Mutation of genes encoding the dynein motors results in ciliary immotility, and is the basis of the human inherited disease Primary Ciliary Dyskinesia (PCD).
Unexpectedly, our identification and analysis of Drosophila auditory neuron genes strongly highlighted Drosophila homologues of known human PCD-causative genes. This is because auditory neurons are the only somatic cells in Drosophila with a motile cilium.
Ciliary motility is a key part of their mechanoreception mechanism, so flies with immotile cilia (e.g. from mutation of a PCD gene homologue) are deaf (as well as male infertile due to immotile sperm).
This led us into an on-going project to discover new Drosophila genes required for ciliary during hearing, with the hypothesis that this would identify candidates for new causative genes of PCD in humans. In collaboration with several human and mouse geneticists (notably Hannah Mitchison, Institute of Child Health, UCL, and Pleasantine Mill, MRC Human Genetics Unit, Edinburgh), this has so far led to the discovery of two new PCD genes (ZMYND10 and HEATR2), with several other candidates currently being worked up (Moore et al., 2014; Diggle et al., 2015).
Many of these new ciliary motility genes seem to function in the cytoplasmic assembly of the dynein motor protein complexes (i.e. they are molecular chaperones), and we are currently using molecular and imaging techniques to probe these functions further.
The Atonal transcription factor is highly conserved. Its mammalian equivalent, Atoh1, is required for the generation of the mechanosensory cells of the inner ear – so-called hair cells, which transduce sound via their stereocilia. Loss of hair cells is the major cause of human sensorineural deafness due to disease, acoustic trauma or ageing. This loss is irreversible – there is no capability for cellular regeneration in mammals.
There is therefore much biomedical interest in manipulating Atoh1 expression or function as a method for promoting hair cell regeneration, e.g. by gene therapy. However, much more needs to be determined concerning Atoh1 function for this to be effective. Based originally on work done in Drosophila, we are studying how Atoh1 function depends on cooperation with other transcription factors, notably Gfi1.
Moreover, Aida Costa (Marie Skłodowska-Curie Fellow) has developed a stem cell model for hair cell generation in the petri dish. Atoh1 is induced in stem cells in combination with two other auditory transcription factors (Gfi1 and Pou4f3), with a resulting highly efficient conversion of the stem cells into hair cells. In collaboration with Sally Lowell (MRC Centre for Regenerative Medicine, Edinburgh) we are currently using this system to analyse Atoh1 function, particularly in identifying its target genes during hair cell generation. We hope that our findings can be used to inform methods of manipulating hair cell regeneration in vivo.
Costa, A, Powell, L.M., Lowell, S., Jarman, A.P. 2016. Atoh1 in sensory hair cell development: constraints and cofactors. Sem. Cell Dev. Biol.
Suslak, T.J., Watson, S., Bewick, G.S., Armstrong, J.D., Jarman, A.P. 2015. Amiloride-sensitive Piezo is essential for mechanotransduction in Drosophila stretch receptor neurons. PLoS One. Doi: 10.1371/journal.pone.0130969
Styczynska-Soczka, K. and Jarman, A.P. 2015. The Drosophila homologue of Rootletin is required for mechanosensory function and ciliary rootlet formation in chordotonal sensory neurons. Cilia 4: 9. DOI: 10.1186/s13630-015-0018-9
Jarman, A.P. 2014. Development of the ear (Johnston’s organ) in Drosophila. In ‘Development of auditory and vestibular systems’. 4th Edition. Ed R. Romand and I. Varela-Nieto. Academic Press, pp31-61.
Price, D., Jarman, A.P., Mason, J.O., and Kind, P. 2011. Building brains: and introduction to neural development. J. Wiley and Son. (‘highly commended’ in BMA Medical Book awards, 2012).
Diggle, C.P., Moore, D.J., Mali G., zur Lage, P.I., Ait-Lounis, A., Schmidts, M., Gautier, P., Yeyati, P., Bonthron, D.T., Carr, I.M., Hayward, B., Markham, A.F., Hope, J.E., von Kriegsheim, A., Mitchison, H.M., Jackson, I.J., Durand, B., Reith, W., Sheridan, E., Jarman, A.P, Mill, P. 2014. HEATR2 plays a conserved role in assembly of the ciliary motile apparatus. PLoS Genet. 10: e1004577. (Joint senior author.)
Hall, E.A., Keighren, M., Ford, M.J., Davey, T., Jarman, A.P., Smith, L.B., Jackson, I.J., Mill, P. 2013. Acute versus chronic loss of mammalian Azi1/CEP131 results in distinct ciliary phenotypes. PLoS Genetics 9: e1003928. Recommended by Faculty of 1000.
Moore, D.M., Onoufriadis, A., Shoemark, A. Simpson, M.A., zur Lage, P.I., de Castro, S.C., Bartoloni, L., Gallone,, G., Petridi, S., Woollard, W.J., Antony, D., Schmidts, M., Didonna, T., Makrythanasis, P., Bevillard, J., Mongan, N.P., Djakow, J., Pals, G., Lucas, J.S., Marthin, J.K., Nielsen, K.G., Santoni, F., Guiponni, M., Hogg, C., Antonarakis, S.E., Emes, R.D., Chung, E.M.K., Greene, N.D.E., Blouin, J-L., Jarman, A.P., Mitchison,,H.M. 2013. Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in human and fly, cause primary ciliary dyskinesia. Am. J. Hum. Genet. 8: 346-356. (Corresponding author.)
Jarman, A.P. and Groves, A.K. 2013. The role of Atonal transcription factors in the development of mechanosensitive cells. Sem. Cell Dev. Biol., 24: 438-447.
Jarman, A.P. 2013. Neurogenesis in Drosophila. In: eLS (electronic Library of Science) (2013). John Wiley and Sons Ltd, Chichester. http://www.els.net/Wiley. DOI:10.1002/9780470015902.a0000825.pub2.
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.