Roles for the stem cell factor LIN41 in ependymal cell function and hydrocephalus
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Hydrocephalus is defined as excessive accumulation of cerebrospinal fluid (CSF) accompanied by expansion of the brain ventricles. The condition can be either congenital or acquired and may be caused by excess CSF production, reduced absorption, or impaired fluid flow. With an incidence of about 1-2 per 1000 children at birth, hydrocephalus is the most common developmental malformation to affect the brain1,2,3. However, at the start of our project only a relatively small number of risk genes responsible for congenital hydrocephalus had been identified, which has limited genetic efforts to better understand the underlying developmental failures. We are studying the molecular functions and developmental roles of the Lin41 gene product (also known by the Gene Symbol Trim71). As a critical downstream target for the miRNA let-7, Lin41 is part of a highly conserved regulatory network important for stem cell differentiation throughout the animal kingdom. However, a great deal remains to be learned about the functions of this regulatory program in mammalian development and its significance for human disease. Null mutations of Lin41 in the mouse are embryonic lethal and cause neural tube closure defects (NTDs), a severe neurodevelopmental failure of brain morphogenesis. The NTD phenotype has been attributed to premature neuronal differentiation, however, the results of targeted deletion in neural progenitors to rigorously test this hypothesis had not yet been reported. To circumvent the lethality of Lin41 deletion in mice and to better understand Lin41 function in embryonic and postnatal brain development, we specifically deleted the Lin41 gene in brain stem cells, specifically the radial glia progenitors of the dorsal telencephalon. We found that more than 25% of the affected mutants develop postnatal hydrocephalus4. Our hypothesis, based on our preliminary work, attributed this result to an uncharacterized function of Lin41 in ependymal cells, a brain-specific type of ciliated cell that lines the ventricles and contributes to CSF flow and homeostasis. Contrary to our hypothesis, in our project we used several experimental techniques to demonstrate that Lin41 is most likely absent in ependymal cells and that ependymal cell function is intact in hydrocephalic Lin41 mouse mutants. The lack of a detectable ependymal phenotype led my group, in collaboration with Kristopher Kahle of Yale University and his colleagues, to characterize the molecular functions of LIN41 in the embryonic neuroepithelium as the basis for hydrocephalus in mouse models and in patients with LIN41 mutations. The results of this collaboration propose a new model suggesting that a primary defect in embryonic neurogenesis can lead to subsequent failure in the morphogenesis of the ventricular system in Lin41 mouse mutants and a significant fraction of congenital hydrocephalus patients.
Publications
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Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature Neuroscience, 25(4), 458-473.
Duy, Phan Q.; Weise, Stefan C.; Marini, Claudia; Li, Xiao-Jun; Liang, Dan; Dahl, Peter J.; Ma, Shaojie; Spajic, Ana; Dong, Weilai; Juusola, Jane; Kiziltug, Emre; Kundishora, Adam J.; Koundal, Sunil; Pedram, Maysam Z.; Torres-Fernández, Lucia A.; Händler, Kristian; De Domenico, Elena; Becker, Matthias; Ulas, Thomas ... & Kahle, Kristopher T.
