Dr Nicholas Cole

Bryson-Richardson, R. J., Berger, S., Schilling, T. F., Hall, T. E., Cole, N. J., Gibson, A. J., Sharpe, J. and Currie, P. D. (2007). FishNet: an online database of zebrafish anatomy. BMC Biol 5, 34.
Cole, N. J. and Currie, P. D. (2007). Insights from sharks: evolutionary and developmental models of fin development. Dev Dyn 236, 2421-31.
Hollway, G. E., Bryson-Richardson, R. J., Berger, S., Cole, N. J., Hall, T. E. and Currie, P. D. (2007). Whole-somite rotation generates muscle progenitor cell compartments in the developing zebrafish embryo. Dev Cell 12, 207-19.
Hall, T. E., Bryson-Richardson, R. J., Berger, S., Jacoby, A. S., Cole, N. J., Hollway, G. E., Berger, J. and Currie, P. D. (2007). The zebrafish candyfloss mutant implicates extracellular matrix adhesion failure in laminin alpha2-deficient congenital muscular dystrophy. Proc Natl Acad Sci U S A 104, 7092-7.
Nihei, Y., Kobiyama, A., Ikeda, D., Ono, Y., Ohara, S., Cole, N. J., Johnston, I. A. and Watabe, S. (2006). Molecular cloning and mRNA expression analysis of carp embryonic, slow and cardiac myosin heavy chain isoforms. J Exp Biol 209, 188-98.
Cole, N. J., Hall, T. E., Martin, C. I., Chapman, M. A., Kobiyama, A., Nihei, Y., Watabe, S. and Johnston, I. A. (2004). Temperature and the expression of myogenic regulatory factors (MRFs) and myosin heavy chain isoforms during embryogenesis in the common carp Cyprinus carpio L. J Exp Biol 207, 4239-48.
Haines, L., Neyt, C., Gautier, P., Keenan, D. G., Bryson-Richardson, R. J., Hollway, G. E., Cole, N. J. and Currie, P. D. (2004). Met and Hgf signaling controls hypaxial muscle and lateral line development in the zebrafish. Development 131, 4857-69.
Tickle, C. and Cole, N. J. (2004). Morphological diversity: taking the spine out of three-spine stickleback. Curr Biol 14, R422-4.
Hall, T. E., Cole, N. J. and Johnston, I. A. (2003). Temperature and the expression of seven muscle-specific protein genes during embryogenesis in the Atlantic cod Gadus morhua L. J Exp Biol 206, 3187-200.
Cole, N. J., Tanaka, M., Prescott, A. and Tickle, C. (2003). Expression of limb initiation genes and clues to the morphological diversification of threespine stickleback. Curr Biol 13, R951-2.
Cole, N. J. and Johnston, I. A. (2001). Plasticity of myosin heavy chain expression with temperature acclimation is gradually acquired during ontogeny in the common carp (Cyprinus carpio L.). J Comp Physiol B 171, 321-6.
Temple, G. K., Cole, N. J. and Johnston, I. A. (2001). Embryonic temperature and the relative timing of muscle-specific genes during development in herring (Clupea harengus L.). J Exp Biol 204, 3629-37.
Wakeling, J. M., Cole, N. J., Kemp, K. M. and Johnston, I. A. (2000). The biomechanics and evolutionary significance of thermal acclimation in the common carp Cyprinus carpio. Am J Physiol Regul Integr Comp Physiol 279, R657-65.
James, R., Cole, N. and Davies, M. (1998). Scaling of intrinsic contractile properties and myofibrillar protein composition of fast muscle in the fish myoxocephalus scorpius L. J Exp Biol 201 (Pt 7), 901-12.
Johnston, I. I. and Cole, N. (1998). Embryonic temperature modulates muscle growth characteristics in larval and juvenile herring. J Exp Biol 201 (Pt 12), 623-46.
Johnston, I. I., Cole, N., Vieira, V. V. and Davidson, I. I. (1997). Temperature and developmental plasticity of muscle phenotype in herring larvae. J Exp Biol 200, 849-68.

Initiation, specification and control of vertebrate limb and muscle development using fish models.

Summary

The overall aim of my research is to use the power of the zebrafish as a model vertebrate to understand normal development and function and to find potential cures of human disorders.

The fundamental question of how different populations form within an embryo has until now, been extremely difficult to address in conventional systems purely due to logistical constraints; mammalian embryos develop in- utero, and direct visual observation of living muscle is all but impossible. In contrast, the zebrafish develops ex-utero and is optically clear during the embryonic and juvenile stages? yielding a unique possibility to examine development in vivo.

In addition, I am interested in generating a detailed understanding of the morphological and genetic control of precursor specification, migration and proliferation that is deployed to generate vertebrate limbs and muscle. The muscle structure of zebrafish represents a relatively simple paradigm where muscle precursors specification and subsequent myoblast elongation, fusion and attachment can be followed in real time. Just as in human embryos, the appendicular muscles of zebrafish are formed from populations of long-range migrating precursors that originate in the somites. In addition, our limbs evolved from the paired fins of ancestral fish, such that initiation and outgrowth of fins is genetically similar to early limb formation. These characteristics make zebrafish a powerful and genetically tractable model system for the analysis of vertebrate limb initiation and muscle development.

Creating and curing fish models of human disorders

In collaboration with Professor Garth Nicholson, ANZAC Research Institute

This program uses powerful molecular and cell biology techniques for the first time to create fish models of inherited neural disorders. The effects of mutations in peripheral nerve genes will be examined to determine the their effect on mobility and development of pathology using fluorescent labeled nerves in living Zebra fish. Nerve degeneration can be seen in real time. The new fish models developed will later be used in high throughput drug screens to develop effective treatments for these previously untreatable diseases. There are more than 50 different genes known to produce inherited neuropathies. Inherited neuropathies are one of the most common human genetic disorders and produce life long disability. Professor Nicholson?s laboratory and clinic has discovered a number of new genes and mutations causing neural disorders. Discovery of the gene mutations causing these disorders continues to proceed rapidly with about 50% of neuropathy genes so far discovered. Each new discovery uncovers new areas of cell biology, leading to publications in leading international journals. This program will allow the effect of the neural gene mutations to be seen for the first time in living organisms and will allow development of high throughput drug screens aiming for future cures. Projects on specific neural genes are available for Honors and PhD students.


Program Type

Honours/Masters/PHD

Synopsis

The fundamental question of how different populations form within an embryo has until now, been extremely difficult to address in conventional systems purely due to logistical constraints; mammalian embryos develop in- utero, and direct visual observation of living muscle is all but impossible. In contrast, the zebrafish develops ex-utero and is optically clear during the embryonic and juvenile stages? yielding a unique possibility to examine development in vivo.

Projects will involve developmental and molecular biology, incorporating modern research techniques (in-situ hybridisation, confocal and electron microscopy, PCR, bioinformatics, fish husbandry, transgenic fish technology, immuno-histochemistry, histology, in-vivo cell lineage tracking) and utilising the zebrafish model system.

I fucus upon the precursor specification, migration and proliferation that is deployed to generate vertebrate limbs and muscle. The fundamental question of how different populations form within an embryo has until now, been extremely difficult to address in conventional systems purely due to logistical constraints; mammalian embryos develop in- utero, and direct visual observation of living muscle is all but impossible. In contrast, the zebrafish develops ex-utero and is optically clear during the embryonic and juvenile stages? yielding a unique possibility to examine development in vivo.The muscle structure of zebrafish represents a relatively simple paradigm where muscle precursors specification and subsequent myoblast elongation, fusion and attachment can be followed in real time using time-lapse photo microscopy. Just as in human embryos, the appendicular muscles of zebrafish are formed from populations of long-range migrating precursors that originate in the somites and express the gene lbx1. In addition, our limbs evolved from the paired fins of ancestral fish, such that initiation and outgrowth of fins is genetically similar to early limb formation. These characteristics make zebrafish a powerful and genetically tractable model system for the analysis of vertebrate limb initiation and muscle development.The long-term outcome of this work will enhance our understanding of limb formation and how stem cell-driven muscle formation and repair occurs in vertebrate embryos. This knowledge will have profound implications for our understanding of the pathology and treatment of limb developmental defects and degenerative muscle disease.*Evolutionary origins of vertebrate limb musculature and the tetrapod transition.Locomotor strategies in terrestrial tetrapod species have evolved from the utilisation of sinusoidal contractions of axial musculature, evident in ancestral fish species, to the reliance on powerful and complex limb muscles to provide propulsive force. Within tetrapod species, a hind limb-dominant locomotor strategy predominates, and its evolution is considered critical for the evident success of the tetrapod transition on to land. A number of fossil forms have provided information on the evolution of the appendicular skeleton of the hind limbs within early tetrapods. Although the fossil record has, in part, charted the evolution of the skeletal framework of the load bearing limbs of tetrapods, it can shed little light on how the accompanying dramatic alterations of the limb musculature required to drive locomotion in terrestrial tetrapods have arisen, as soft tissues are rarely preserved within the fossil record. In order to examine this question it is necessary to uncover the mechanisms that generate limb and fin muscles within extant species strategically positioned within the vertebrate phylogeny. We are examining this question by describing the mechanisms utilised to generate fin muscles within extant fish species positioned at critical points within the vertebrate phylogeny (sharks, paddlefish and lungfish).

MUSCLE AND LIMB/FIN DEVELOPMENT AND EVOLUTION
Initiation, specification and control of vertebrate limb and muscle development

The general aim of my research is togenerate a detailed understanding of the morphological and genetic control of precursor specification, migration and proliferation that is deployed to generate vertebrate limbs and muscle. our limbs evolved from the paired fins of ancestral fish, such that initiation and outgrowth of fins is genetically similar to early limb formation. These characteristics make zebrafish a powerful and genetically tractable model system for the analysis of vertebrate limb initiation and muscle development.
The muscle structure of zebrafish represents a relatively simple paradigm where muscle precursors specification and subsequent myoblast elongation, fusion and attachment can be followed in real time using time-lapse photo microscopy. Just as in human embryos, the appendicular muscles of zebrafish are formed from populations of long-range migrating precursors that originate in the somites. The long-term outcome of this work will enhance our understanding of limb formation and how stem cell-driven muscle formation and repair occurs in vertebrate embryos. This knowledge will have profound implications for our understanding of the pathology and treatment of limb developmental defects and degenerative muscle disease.
Embryonic origins of vertebrate muscle

Limb muscles are formed by the long-range migration of precursor cells from the developing embryonic somites. Zebrafish fin muscle precursors possess molecular and morphogenetic identity with these limb muscle precursors. The mechanisms controlling precursor specification, initiation, migration and differentiation are yet to be determined. In addition the embryonic origin of many other muscle groups is still unknown. We now have a unique opportunity to utilise the resolving power of novel transgenic tools to permanently in vivo track the derivatives of muscle precursors in real time and therefore determine the spatial and temporal origins of migratory muscles. A deeper understanding of muscle lineage specification will provide insights into the normal, as well as pathological, aspects of skeletal muscle, heart and craniofacial development.

Determining the position and timing of limb initiation.

The developmental origins and molecular processes that generate our legs and associated musculature have not been fully defined. To date, only two hind-limb specific genes have been discovered (Pitx1 & Tbx4). Tetrapod hind-limbs evolved from the pelvic fins of ancestoral fish and the signaling centres involved in limb formation are similarly involved in fin formation, for example, Pitx1 and Tbx5 are required for pelvic fin development. Therefore, examining the genetic control of pelvic fin development will shed light upon the developmental mechanisms of correct hind limb formation. We will utilize the power of the zebrafish vertebrate model to investigate the genes responsible for pelvic fin specification, initiation and outgrowth. In addition, we have pelvic fin and pectoral fin (evolutionary forerunner to tetrapod hind and fore-limb respectively) deficient zebrafish. Elucidating the gene or signaling centre responsible for these morphologies will highlight genes involved in limb development and disease.

Creating and curing fish models of human neural disorders

There are more than 50 different genes known to produce inherited neuropathies. Inherited neuropathies are one of the most common human genetic disorders and produce life long disability. This program uses powerful molecular and cell biology techniques for the first time to create fish models of inherited neural disorders. The effects of mutations in peripheral nerve genes will be examined to determine the their effect on mobility and development of pathology using fluorescent labeled nerves in living zebrafish. Nerve degeneration can be seen in real time. The new fish models developed will later be used in high throughput drug screens to develop effective treatments for these previously untreatable diseases. Professor Nicholson?s laboratory and clinic has discovered a number of new genes and mutations causing neural disorders. Discovery of the gene mutations causing these disorders continues to proceed rapidly with about 50% of neuropathy genes so far discovered. Each new discovery uncovers new areas of cell biology, leading to publications in leading international journals. This program will allow the effect of the neural gene mutations to be seen for the first time in living organisms and will allow development of high throughput drug screens aiming for future cures.

Additional Information

Zebrafish are our model organism, increadibly these small fish are an amazing system to answer many questions of human disease. The laboratory has a brand new 'state of the art zebrafish facility'. In addition I examine sharks, paddlefish and lungfish for an evolutionary view point. I will provide an encouraging, interactive and enjoyable environment for you to development as a research scientist. I am very open to your own ideas and questions.