The embryonic neural plate is comprised of undifferentiated neural precursor cells that give rise to the central nervous system. In the anterior region of the neural plate, cells assume a telencephalic fate and eventually generate the adult cerebral hemispheres. The goal of this research is to understand why these anterior cells adopt a telencephalic fate and what promotes their survival and proliferation. The anterior neural ridge (ANR) that demarcates neuroectoderm from underlying ectoderm is necessary and sufficient to induce telencephalic character to neural plate cells. This ridge secretes Fibroblast Growth Factors (FGFs) and, at least in zebrafish, a Wingless-Int (WNT) antagonist encoded by the tlc gene. Knockdown of tlc or loss of other WNT antagonists (axin, six3) results in loss of telencephalic markers in zebrafish, indicating that low WNT signaling is necessary for telencephalon induction. In mice, it remains unclear if low WNT signaling is necessary for telencephalon induction. FGFs may also play a role in inducing the telencephalon, although no FGF signaling mutant in any species has yet been reported to result in the loss of the telencephalon. Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline, and that FGF signaling mediates organizer activity by inducing and patterning the telencephalic neuroepithelium and maintaining its cells alive. In this proposal, using genetic and explant culture approaches, we test whether WNTs regulate telencephalon induction in the mouse and how this pathway interacts with the FGF and BMP pathways in regulating cell fate, survival, and proliferation.
At about the fifth week of gestation in humans, the anterior part of the emerging central nervous system (the neural plate) begins to express genes that characteristically mark the embryonic cerebrum, or telencephalon. Shortly after, the neural plate closes on itself to form the neural tube. At this stage the telencephalon becomes morphologically apparent as an inflated sheet of cells surrounding bilateral ventricles. The telencephalon gives rise primarily to the neocortex and hippocampus dorsally, which we use for our highest cognitive functions, and the basal ganglia ventrally, which we use for motor coordination and emotional functions. In humans, the absence of telencephalic derivatives at birth, atelencephaly, is suspected in some cases of being an inherited recessive disorder, but the mutant genes are unknown. Atelencephaly may be part of a continuous spectrum of forebrain truncations including the more severe aprosencephaly in which both telencephalon and thalamus are missing. The lack of available families with significant numbers of cases makes research into the genetic causes of these disorders difficult, underscoring the importance of animal models, particularly mouse models, in identifying the genetic pathways that lead to telencephalic induction and maintenance. Identifying these pathways will lead to new strategies for diagnosing and treating forebrain truncation disorders, as previously described for neural tube defects. In this proposal, using a genetic approach in the mouse, we directly test the function of three signaling pathways, WNT, FGF, and BMP, in the initial formation of the telencephalon. Moreover, by examining the interaction of these pathways, we are uncovering interdependencies among them which have broad implications for understanding how development of other tissues is regulated, how proliferation in hyperplastic tissues can be misregulated, and how these abnormal tissues can be targeted with new therapies.
|Hébert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279|
|Antoine, Michelle W; Vijayakumar, Sarath; McKeehan, Nicholas et al. (2017) The Severity of Vestibular Dysfunction in Deafness as a Determinant of Comorbid Hyperactivity or Anxiety. J Neurosci 37:5144-5154|
|Nandi, Sayan; Gutin, Grigoriy; Blackwood, Christopher A et al. (2017) FGF-Dependent, Context-Driven Role for FRS Adapters in the Early Telencephalon. J Neurosci 37:5690-5698|
|Nandi, Sayan; Chandramohan, Dhruva; Fioriti, Luana et al. (2016) Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain. Proc Natl Acad Sci U S A 113:12697-12702|
|Kang, Wenfei; Balordi, Francesca; Su, Nan et al. (2014) Astrocyte activation is suppressed in both normal and injured brain by FGF signaling. Proc Natl Acad Sci U S A 111:E2987-95|
|Hébert, Jean M (2013) Only scratching the cell surface: extracellular signals in cerebrum development. Curr Opin Genet Dev 23:470-4|
|Antoine, Michelle W; Hübner, Christian A; Arezzo, Joseph C et al. (2013) A causative link between inner ear defects and long-term striatal dysfunction. Science 341:1120-3|
|Kang, Wenfei; Hebert, Jean M (2012) A Sox2 BAC transgenic approach for targeting adult neural stem cells. PLoS One 7:e49038|
|Fernandes, Marie; Antoine, Michelle; Hébert, Jean M (2012) SMAD4 is essential for generating subtypes of neurons during cerebellar development. Dev Biol 365:82-90|
|Paek, Hunki; Antoine, Michelle W; Diaz, Frank et al. (2012) Increased ?-catenin activity in the anterior neural plate induces ectopic mid-hindbrain characteristics. Dev Dyn 241:242-6|
Showing the most recent 10 out of 13 publications