Evolution and Development Laboratory
Lab head: Nicholas Cole
Location: W315 Sydney Medical School, Anderson Stuart Building F13
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; model mammalian embryos (mouse) 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 the living organisms using beautiful transgenic fish expressing fluorescent proteins in vivo.
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.
Initiation, specification and control of vertebrate limb and muscle development
The general aim of my research is to generate 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 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 lbx2.
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).
Understanding and Fishing for Cures for Neurodegenerative Disease.
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, one of the main strengths of the zebrafish model, and is simply breathtaking to see. 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. In collaboration with Professor Nicholson’s laboratory and clinic which 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 are available for Honors and PhD students.
Lab members: Dr. N Cole (head), Miss E.Don (Ph.D), Mr. Udara Bandara (Hons)
Research approach equipment: Brand new state of the art PC2 certified aquatic organism facility and lots more besides.
Determining the position and timing of limb initiation
Primary supervisor: Nicholas Cole
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 fore-limb) deficient zebrafish. Elucidating the gene or signaling centre responsible for these morphologies will highlight genes involved in limb development and disease.
Discipline: Anatomy & Histology
Keywords: limb and fin development, Musculoskeletal diseases, zebrafish
Contact: Email Nicholas Cole