College of Arts and Science
As the central nervous system develops, neurons often migrate extensively before assembling the circuits that drive cognitive and motor function. Within the vertebrate hindbrain, Facial Branchiomotor (FBM) neurons migrate caudally from rhombomere 4 (r4) to r6 and generate the circuits that drive facial and jaw movements. While several components of the Wnt/PCP (Planar Cell Polarity) pathway have been investigated for their roles in initiating FBM neuron migration, much less is known regarding the mechanisms that determine directionality. Our lab discovered that in mice lacking the Wnt/PCP component Celsr1, many FBM neurons inappropriately migrate rostrally into r3. Tissue-specific knockouts indicate that Celsr1 is functioning non-cell autonomously within the ventricular zone rostral to r4 in order to prevent rostral migration.
Intriguingly, Celsr1 and a potential chemoattractant gene Wnt5a are expressed in overlapping domains within the rostral hindbrain. Based on these findings, we hypothesized that in the wildtype hindbrain, Celsr1suppresses Wnt5a function rostral to r4 to block the inappropriate rostral migration of FBM neurons. I have successfully tested three predictions of this hypothesis in my dissertation.
First, if WNT5A is functioning as a chemoattractive cue to induce rostral migration in Celsr1 mutants, then rostral migration should be suppressed in Celsr1; Wnt5a double knockouts. Indeed, FBM neurons in Celsr1; Wnt5a double knockout embryos never migrated rostrally. Second, if WNT5A is acting as chemoattractive source in the rostral hindbrain of Celsr1 knockouts, then rostral migration should be dependent on the function of DISHEVELED, an essential downstream component of Wnt signaling. FBM neurons migrated rostrally toward WNT5A-coated beads in wildtype hindbrain explants, demonstrating that excess WNT5A can overcome suppression mediated by endogenous Celsr1 expression. Importantly, rostral migration towards WNT5A-coated beads was reduced in Dvl2 mutants, suggesting that the WNT5A-mediated chemoattraction of FBM neurons is dependent on Wnt5a-Dvl2 signaling. Third, our hypothesis predicts that rostral migration of FBM neurons would be greatly enhanced in Celsr1 mutants overexpressing Wnt5a in r3. When a Wnt5a gain-of-function allele was used to overexpress Wnt5a in rx3 of Celsr1 mutants, the population of rostrally migrating FBM neurons was substantially larger than in control mutants, further supporting the chemoattractive model. These results reveal a novel role for a Wnt/PCP component in regulating neuronal migration by suppressing chemoattraction.
Asante, E., Hummel, D., Gurung, S., Kassim, Y.M., Al-Shakarji, N., Palaniappan, K., Sittaramane, V., Chandrasekhar, A. Defective Neuronal Positioning Correlates With Aberrant Motor Circuit Function in Zebrafish (2021) Frontiers in Neural Circuits, 15, art. no. 690475. DOI: 10.3389/fncir.2021.690475
Gurung, S., Asante, E., Hummel, D., Williams, A., Feldman-Schultz, O., Halloran, M.C., Sittaramane, V., Chandrasekhar, A. Distinct roles for the cell adhesion molecule Contactin2 in the development and function of neural circuits in zebrafish (2018) Mechanisms of Development, 152, pp. 1-12. DOI: 10.1016/j.mod.2018.05.005
Devynn plans to secure an industry or academic research position working with mouse models of development and/or disease.
Ph.D. Candidate - Chandrasekhar Lab
Division of Biological Sciences
University of Missouri