Rare Diseases: Models & Mechanisms Network

Basic Information

First Name
Last Name
Organization
Department
Website	https://sunnybrook.ca/research/team/member.asp?t=13&m=756&page=530

Contact Information

Email	cschuurm@sri.utoronto.ca
Phone	416-480-6100 ext 3266

About My Research

I study neural development, with a focus on the neocortex and retina. I am interested in the molecular mechanisms that influence neural cell fate decisions and tissue morphogenesis. My research program focuses on transcription factors involved in neuronal differentiation, and on signaling molecules that control tissue morphogenesis. With respect to rare disorders, I study PTEN Hamartoma Tumour Syndrome (PHTS), a heterogeneous group of rare, autosomal dominant disorders that are characterized by germline mutations in PTEN, a protein and lipid phosphatase. A major hallmark of these syndromes is the formation of hamartomas, which are benign tissue overgrowths comprised of disorganized ‘normal’ cells indigenous to the tissue. Hamartomas form in all embryological lineages and include soft tissue lesions, which lead to significant morbidity and mortality, and central nervous system lesions, associated with neurological deficits. A striking feature of these disorders is their phenotypic heterogeneity, with hamartomas forming in multiple or only a few tissues. How this heterogeneity arises is unknown, but a leading hypothesis is that second hit mutations create cohorts of mutant cells that act non-cell autonomously to create disorder in neighboring wild-type tissue. We created a mouse model that recapitulates this disease process, demonstrating that Pten deletion in the peripheral retina produces a hamartoma-like lesion in the ‘wild-type’ central retina. Furthermore, we have evidence that Pten mutant cells may mediate these non-cell autonomous effects by perturbing the intracellular processing of proteins. We aim to use our PHTS mouse model to investigate our hypothesis of non-cell autonomy, and to test for defects in protein processing, focusing on exosome secretion and autophagy. We will also test the therapeutic effects of targeting these protein processing pathways.

Human Organ Systems

Reactome Pathways

Term ID	Term Name	Term Definition
R-HSA-9675143	Diseases of the neuronal system	Diseases of the neuronal system can affect sensory cells and transmission of signals between sensory cells and sensory neurons (Martemyanov and Sampath 2017), transmission of signals across electrical and chemical synapses in the nervous system (Picconi et al. 2012, Yin et al. 2012, Kida and Kato 2015), and transmission of signals between motor neurons and muscle cells (Sine 2012, Engel et al. 2015).<br><br>We have so far annotated diseases of visual phototransduction due to retinal degeneration caused by defects in the genes involved in the retinoid cycle (Travis et al. 2007, Palczewski 2010, Fletcher et al. 2011, den Hollander et al. 2008).
R-HSA-9675108	Nervous system development	Neurogenesis is the process by which neural stem cells give rise to neurons, and occurs both during embryonic and perinatal development as well as in specific brain lineages during adult life (reviewed in Gotz and Huttner, 2005; Yao et al, 2016; Kriegstein and Alvarez-Buylla, 2009).
R-HSA-112316	Neuronal System	The human brain contains at least 100 billion neurons, each with the ability to influence many other cells. Clearly, highly sophisticated and efficient mechanisms are needed to enable communication among this astronomical number of elements. This communication occurs across synapses, the functional connection between neurons. Synapses can be divided into two general classes: electrical synapses and chemical synapses. Electrical synapses permit direct, passive flow of electrical current from one neuron to another. The current flows through gap junctions, specialized membrane channels that connect the two cells. Chemical synapses enable cell-to-cell communication using neurotransmitter release. Neurotransmitters are chemical agents released by presynaptic neurons that trigger a secondary current flow in postsynaptic neurons by activating specific receptor molecules. Neurotransmitter secretion is triggered by the influx of Ca2+ through voltage-gated channels, which gives rise to a transient increase in Ca2+ concentration within the presynaptic terminal. The rise in Ca2+ concentration causes synaptic vesicles (the presynaptic organelles that store neurotransmitters) to fuse with the presynaptic plasma membrane and release their contents into the space between the pre- and postsynaptic cells.

Mouse Research Focus

I use mouse as a model organism. We have a conditional knockout of Pten that can be crossed with different cre driver lines to generate models of Pten hamartoma tumor syndrome.

Genes
Terms

Gene ID	Symbol	Name	Tier
22634	Plagl1	pleiomorphic adenoma gene-like 1	TIER2
19211	Pten	phosphatase and tensin homolog	TIER2
18014	Neurog1	neurogenin 1	TIER2
17172	Ascl1	achaete-scute family bHLH transcription factor 1	TIER2
11924	Neurog2	neurogenin 2	TIER2

Term	Name	Aspect	Overlap	Size

Publications

PubMed ID	Title
27605619	Pten Regulates Retinal Amacrine Cell Number by Modulating Akt, Tgf?, and Erk Signaling.
29716894	Hamartoma-like lesions in the mouse retina: an animal model of <i>Pten</i> hamartoma ...
22403711	Cell-type specific roles for PTEN in establishing a functional retinal architecture.

Last modified on May 10, 2024.