Laboratory of Developmental Genetics
The development of the embryo into a mature organism is a fascinating and complex process requiring of thousands of genes.
In recent years, it has become clear that the genetic program that controls vertebrate development is highly conserved. Therefore, the developmental role of genes that are associated with congenital abnormalities in humans can be investigated using other vertebrate species, including mice.
The overall aim of our laboratory is to understand the function of genes that cause neurodevelopmental disorders through the generation and analysis of knock-out and transgenic mouse models.
Our current research focuses on the transcription factor gene SOX3, which is associated with the childhood syndrome X-linked Hypopituitarism (XH). Patients with XH suffer from variable mental retardation and dwarfism due to abnormal development of the central nervous system including the hypothalamic-pituitary axis. We have previously shown that Sox3 is expressed in the developing mouse brain and that patients with XH have mutations or duplications in this gene. Our collaborative studies using a Sox3 knock-out (null) mouse have also shown that this gene is a key regulator of Central Nervous System (CNS) development and is essential for normal development of the cortex, hypothalamus and pituitary.
Development and Analysis of Mouse Models for X-linked Hypopituitarism
To understand the developmental and pathological basis of XH, we have generated transgenic mice that contain extra copies of the Sox3 gene. These mice have variable dwarfism and developmental defects of the CNS including ventricular enlargement and absence of the hippocampus and midline structures. These abnormalities arise from defective development of the forebrain during embryogenesis.
We are currently investigating the mechanism responsible for this embryonic defect through molecular and cellular analysis of mutant and transgenic embryos. In addition, we are using microarray technology to identify Sox3 target genes, which will help us to unravel the genetic pathways that are controlled by this important transcription factor.
Our collaborative studies with colleagues in Europe have shown that some XH patients have polyalanine expansion mutations in SOX3. Polyalanine expansion mutations have recently been recognised as an important new class of mutations and have been identified in eight transcription factor genes that are associated with congenital syndromes in humans.
Our functional analysis of wildtype and mutant SOX3 proteins in cell lines and chick embryos indicate that mutant proteins misfold and generate cytoplasmic and nuclear aggregates with poor transcriptional activity. To determine the impact of mutant SOX3 protein on neurodevelopment, we are using targeted mutagenesis to generate Embryonic Stem Cells and mice that contain a Sox3 polyalanine expansion allele. Comprehensive in vitro and in vivo analyses of neuro-differentiation in these mutant ES cells and mice will provide key insights into the functional consequences of Sox3 polyalanine expansions and the molecular pathology of patients with XH.