Mammalian Development and developmental disease.
It is estimated that 6% of children worldwide are born with a serious birth defect or congenital disorder. Our group is seeking to understand the developmental pathways that underlie some of these disorders. We combine high throughput sequencing technologies and molecular techniques to refine and further understand the pathways identified in scoliosis and clubfoot using a mouse model. Projects are available combining molecular and developmental biology methods to advance understanding of the etiology of these disorders.
Sex-dimorphic brain development
In addition to reproductive development and development of primary sex characteristics, a number of sex-related changes occur in the brain, however these have been very poorly characterized at the developmental level. The adult male brain is 11% larger (by volume) compared to a female adult, and a number of sub-regions of the brain are reported as being structurally different in males and females, including amygdala, hippocampus and basal ganglia. One of the most dramatic differences between development of the male and female brains is the rate of maturation. Data from longitudinal studies has shown that the female brain reaches peak development at 10.5 years compared to males at 14.5 years old. It has been proposed that these biological differences between the male and female brain underlie many human sex-biased behaviours and disorders.
Developmental rate has long been associated with the pathology of some neurological disorders. Abnormal brain growth is found in both male and female autism patients; a brain from an autistic individual develops at a much faster rate from infancy and this slows with age. Excess neuron numbers (over 40% in some autistic brain regions) are most likely due to abnormal prenatal development and are proposed to be one of the earliest indicators of the origin of autism. In contrast, brain growth in patients with ADHD is slower compared to other neurodevelopmental disorders or unaffected children, particularly in the cerebrum where cognitive processes are managed.
This research and others raises a number of questions about processes underlying both sex-bias and treatment of neurological disorders. However, we first need to understand some of the developmental processes that control the rate and sex-bias of brain development in order to understand how developmental trajectories differ between sexes and how this impacts on disease and injury susceptibility.
This project includes microRNA (miRNA analysis), expression studies (in situ hybridization, qPCR), immunohistochemistry and mouse models.
Urogenital ridge development and disorders of sex determination.
The distinction between sexes is one of the most obvious example of morphological dimorphism in the animal kingdom, that highlights one of the most crucial fate decisions made in utero; to become a male or female. In order for sexual development to occur, the formation of gonad anlagen is first required. Mammalian gonads are unique among the animal kingdom as they arise from a bipotential progenitor gonadal tissue called the urogenital ridge (UGR). However, very little is known about how the molecular networks that shape its formation and the molecular preparations made to allow for two developmental trajectories. The LIM-homeobox gene, Lhx9 is among only a handful of genes known to be required for UGR formation, but it’s regulatory network, and that of the UGR is poorly understood.
The aim of this project was to investigate the relationship between the correct gonadal morphogenesis and malformation. To gain a better understanding of the gene networks and pathways that are required for the formation of the UGR, ChIP sequencing was preformed to investigate the factors involved in this process on a genome wide scale. We are also identifying the molecular pathways involved in gonadogenesis by further investigating the Lhx9-/- knockout mice model.
The role of the Lbx1 gene and puberty in the etiology of idiopathic scoliosis.
We are working in collaboration with a human molecular genetics group at the Texas Rite Hospital for Children (TSRHC) who have identified several genes associated with two common childhood disorders, clubfoot and scoliosis in patients referred to their clinic. Scoliosis is the most common type of spine deformity in children and is classed as an abnormal lateral side curvature of the spine of 10° or greater that is not a result of injury. Scoliosis occurs in around 1-3% of the population worldwide. The most common form of scoliosis is idiopathic scoliosis (IS), which occurs in otherwise healthy children with no obvious structural problems with the spinal column. The majority of IS cases develop in adolescence (AIS), where spine curvature develops between the ages of 11-18 years in association with the adolescent growth spurt. Despite AIS being a severe and debilitating disease, its biological origin is poorly understood. Current clinical approaches are compromised by a lack of knowledge about how AIS develops, and how it might be mitigated. This research project aims to understand AIS pathogenesis at the molecular and cellular level in order to transform the way AIS treatment is currently managed in the clinic.
This project will involve using mouse models (including CRISPR-CAS9 knockouts), genomics (ChIP-seq) and gene expression analyses.
Whole body regeneration in only 8 days.
Multicellular animals capable of varying degrees of regeneration are distributed widely throughout most metazoan phyla. In its most dramatic form, whole-body regeneration (WBR), an entire adult organism regenerates from only a small number of somatic cells. Regeneration ability appears to inversely correlate with body and tissue complexity; consequently, adult stem cells in human organs can act to repair damage but have a limited ability to fully restore structure and function. However, a striking exception to this relationship is the invertebrate colonial sea squirt Botrylloides leachi. Tunicates, such as B. leachi, possess a chordate body plan and are considered the closest phylogenetic relative of vertebrates. Botryllid colonies consist of adults (zooids) sharing a common vascular system embedded in a gelatinous matrix (tunic). Minute fragments of this vasculature containing only a few hundred cells are capable of regenerating a whole functional adult organism within 8 days. Why is it that in B. leachi, a stem cell population can restore an entire adult body plan (including the germ line), but adult stem cells in more complex animals can merely repair it? This project will involve using transcriptomics, siRNA and gene expression analyses.