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Can bad Wnt signaling derail brain growth?
University of North Carolina (UNC) School of Medicine researchers have pinpointed a specific problem in cell signalling between progenitor cells. Progenitor cells are stem cells that are no longer "totipotent," meaning they had the potential to become any type of cell in the body, including sperm or egg. But now, they are "pluripotent" cells with a limited ability to differentiate into specific "target" cell types — a step crucial towards tissue formation.
As neurons are being generated, the brain is being organized. Deleted progenitor cells can thus cause abnormal brain development. The embryonic brain develops through an incredibly complex cascade of cellular events, beginning with progenitor cells generating neuron growth and development of the cortex. In this complex process, if one tiny protein doesn't do its job - the brain can develop abnormally. Research led by Eva Anton PhD, professor of cell biology and physiology at the UNC School of Medicine, reveals how deletion of the protein APC in progenitor cells leads to massive disruption of the Wnt protein pathway. This cascade of signals is also linked to genes associated with autism. The work appears in Science Direct.
The Anton lab findings support other autism studies suggesting that the long path towards autism begins when development of progenitor cells in the cerebral cortex become disrupted. Two studies led Anton to suspect something within Wnt signaling between progenitor cells might be the culprit.
"Although our experiments were done in mouse genetic models, human APC mutations have previously been associated with autism. These mutations disrupt the ability of brain progenitor cells to respond appropriately to environmental cues necessary for them to divide, generate and guide neurons during brain development."
In the developing embryonic brain, Wnt triggers a degradation complex inside progenitor cell cytoplasm destroying the ß-catenin protein. ß-catenin is important because it affects how neurons are created and how neurons channeled into position within the brain. Given the important role Wnt signaling has in creating and determining placement of neuron cells, researchers are finding Wnt signaling can also influence various cancers.
Experiments led by Naoki Nakagawa PhD,in Anton's lab, found that when APC protein is deleted, ß-catenin is left unchecked, triggering unregulated patterns of gene expression, i.e. gene function, in progenitor cells. When Nakagawa reduced (restricted) ß-catenin in mice without APC, the mice developed normally. In another experiment in mice with APC, Anton's team hyper-activated ß-catenin independent of APC and again mouse brains didn't develop properly. Anton: "This showed us that it truly was the deregulation of ß-catenin that caused problems. It's APC in that protein complex that's key to proper regulation."
"We need ß-catenin to get tagged for destruction by that protein complex. If it doesn't, then Wnt abnormally activates genes in progenitors, causing them to behave abnormally."
Although this work suggests neuropsychiatric conditions might arise due to mutations during embryonic brain growth, Anton believe's it's too early in the research to say 'nothing can be done' to address these early Wnt signaling problems, or that there is a direct relationship to the rise of autism in children.
"We now want to focus on genes. These are genes we know can cause autism. Some of these genes are expressed in progenitor cells. We want to see if deregulation of Wnt signaling triggers changes in autism gene syndrome expression and function in human progenitor cells,"
For these studies, Anton's lab uses mice as her model animals. If the mice show Wnt signaling in progenitor cells affects autism genes, Anton's lab could then test human progenitor cells grown as "minibrain organoids" in order to study how progenitor cells are affected in autism patients. Anton: "Although progenitor defects cannot be treated in mature brain neurons, with such studies we can at least pinpoint what is changing in people who develop autism due to subtle but crucial brain changes before birth."
Researchers have now identified many highly penetrant genetic risk factors for autism spectrum disorder (ASD). Some of these genes encode synaptic proteins, lending support to the hypothesis that ASD is a disorder of synaptic homeostasis. Less attention, however, has been paid to the genetic risk factors that converge on events that precede synaptogenesis, including the proliferation of neural progenitor cells and the migration of neurons to the appropriate layers of the developing neocortex. Here I review this evidence, focusing on studies of mutant mouse phenotypes, human postmortem data, systems biological analyses, and non-genetic risk factors. These findings highlight embryonic neurogenesis as a potentially important locus of pathology in ASD. In some instances, this pathology may be driven by alterations in chromatin biology and canonical Wnt signaling, which in turn affect fundamental cellular processes such as cell-cycle length and cell migration. This view of ASD suggests the need for a better understanding of the relationship between variation in neuron number, laminar composition, and the neural circuitry most relevant to the disorder.
Other authors included postdoc Keiko Yabuno-Nakagawa, PhD, lab manager Robin Taylor, and former Anton lab postdocs Jingjun Li, PhD, Martin Cowles, PhD, and Tae-Yeon Eom, PhD.
Keywords: AutismCell cycleDe novo mutationGeneticsNeurogenesisNeocortex
The National Institutes of Health funded this research. Return to top of page
LEFT Image shows typical brain cell organization in normal mice. RIGHT image shows how deleting
the APC protein in progenitor cells upsets the normal organization of neurons and their migration
throughout the brain. Image Credit: Anton Lab, UNC School of Medicine.