Regulation of proliferation, differentiation, and migration of neural progenitor cells is critical for the normal development of the nervous system. Many factors can influence these events, including the neurotrophin family of factors. These processes have been extensively studied in cerebellar granule cell progenitors (GCP), the most abundant cell type in the brain, which undergo much of their development postnatally. GCPs proliferate in external granule layer (EGL), a transient layer of the cerebellum, and migrate internally to form the internal granule layer (IGL). In the external part of the EGL these cells proliferate, while in the internal part of the EGL the cells exit the cell cycle and start to migrae toward the inside of the developing cerebellum. The p75 neurotrophin receptor (p75NTR) is highly expressed in the EGL during development of the cerebellum, and is absent once the cells begin to migrate. The function of p75NTR in this developing neuronal population has not been defined. Our preliminary data demonstrate that this receptor promotes withdrawal from the cell cycle and inhibits migration, and mice lacking this receptor show increased markers of proliferation, delayed cell cycle exit, and an enlarged cerebellum. We propose that p75NTR plays a crucial role in regulating the timing of the transition of granule cell progenitors from a proliferating to a migrating population. The p75NTR-/- mice have structural deficits in the adult cerebellum, and our preliminary data indicate that adult mice lacking p75NTR in the EGL during development show deficits in motor behavior, suggesting that modulation of these developmental events have long-lasting consequences in the adult. Thus, we expect to define novel roles for p75NTR in the developing brain that have long-term consequences for cerebellar structure and function.
Normal brain development depends on the appropriate transition from a dividing to a migrating population of neuronal progenitors; disturbances in this process may result in inappropriate connectivity leading to cognitive or motor dysfunction. The p75 neurotrophin receptor is highly expressed on the dividing granule cell progenitors in the cerebellum, and it is absent once these cells begin to migrate. Our preliminary data support an important role for this receptor in the appropriate timing of the transition from a proliferating t a migrating population. Mice lacking this receptor show abnormalities in the development of the cerebellum, which lead to persistant deficits in cerebellar structure and motor behavior in the adult.
| Zanin, Juan Pablo; Abercrombie, Elizabeth; Friedman, Wilma J (2016) Proneurotrophin-3 promotes cell cycle withdrawal of developing cerebellar granule cell progenitors via the p75 neurotrophin receptor. Elife 5: |
