Anna Marie Kenney, PhD

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During vertebrate development, precursor cells respond to extracellular signals, which promote their proliferation or direct them to leave the cell cycle and differentiate, given an appropriate cellular competency state. Direct and indirect interactions between mitogenic and maturation pathways influence central nervous system (CNS) precursor cell decisions to divide or commit to a terminal differentiation program. Alterations in the balance between pro-proliferative and pro-differentiation signals may set the stage for cancer by establishing conditions conducive for cell transformation, or may cause precocious cell cycle exit, leading to developmental disorders. In later life, neuronal death can be marked by evidence of aberrant cell cycle re-entry. The theme of our lab is modeling cell division in primary neural precursors in vitro and to learn how cell cycle dysregulation contributes to human CNS disease, particularly cancer.

[Enlarge Image] N-myc phosphorylation in metaphase cerebellar neural precursor in culture. Sonic hedgehog is required for cerebellar precursor proliferation in vivo and in vitro, and has been implicated in medulloblastoma. Phosphorylation promotes N-myc degradation, a prerequisite for cerebellar neural precursor cell cycle exit and differentiation. Red: phosphorylated N-myc; green: tubulin; blue: chromatin.

Medulloblastoma is the most common malignant solid childhood tumor. These tumors arise from precursor cells of the developing cerebellum, a brain region which undergoes rapid expansion after birth. Current treatments for these tumors include surgery, radiation, and chemotherapy, which cause lasting physical, cognitive, and psychological effects. Thus, development of more optimal treatments is of great importance. Links between neurodevelopmentally critical signaling pathways (such as those activated by Sonic hedgehog, Notch, wnt, and insulin-like growth factor) and medulloblastoma formation or maintenance have been made. Major projects in the lab focus on neural precursor proliferation regulation by these signaling pathways. Our efforts include investigation of how such pathways interact with each other and with the cell cycle regulatory machinery; characterization of specific pathway targets; functional analysis of the pathways' effectors; and genetic manipulation of these pathways and their targets in mice to better understand brain development, cancer, and CNS pathologies.