Rosalind Segal

Department of BCMP
Dana-Farber Cancer Institute
44 Binney Street, Dana 620
Boston, MA 02115
Tel: (617) 632-4737
Fax: (617) 632-2085
Email: Rosalind_segal@dfci.harvard.edu

Web Page: The Segal Lab Page
4 postdoctoral fellows, 2 graduate students

We are interested in neural development -from neural stem cells to functional neurons that are part of a neural circuit. Neural stem cells are self-renewing precursors capable of giving rise to additional stem cells and to differentiated cells. A feature of the specialized niches where stem cells are found in the developing and mature brain is that they contain both critical protein growth factors and specialized proteoglycans. Sonic Hedgehog (Shh) is one such growth factor. Using genetic approaches to target interactions between Shh and proteoglycans, we find that proteoglycan interactions are selectively needed for a proliferative response to Shh. We are studying how Shh-proteoglycan interactions regulate neural stem cell and precursor proliferation. As mutations that activate the Shh signaling pathway cause brain tumors and other cancers, Shh-proteoglycan interactions are likely to be important in oncogenesis.

The migration of neural precursor cells away from the mitogenic stem cell niche enables the cells to exit the cell cycle, and differentiate. Our studies have identified brain-derived neurotrophic factor (BDNF) as a critical chemotactic factor for neural precursors. It is surprising that precursors can polarize and move in the correct direction in response to a very shallow gradient of BDNF. We are using both in vivo and in vitro approaches to determine how precursors perceive and respond to this gradient. We find that regulated trafficking of vesicles is required for precursors to polarize and migrate up a shallow BDNF gradient. We are investigating the mechanisms of vesicle trafficking that amplify the perceived gradient, and enable precursors to migrate to the correct position.

As differentiated neurons reach their destinations they form synapses and become incorporated into functional circuits. Neurons that form connections survive due to the actions of neurotrophins, while neurons that fail to connect undergo apoptosis. We are interested in understanding how neurotrophins allow the selective survival of neurons that are part of a circuit. We found that neurotrophin receptors must be activated, internalized, and transported by a dynein motor in order to transmit a survival signal from the synapse to the nucleus. We are investigating the molecular mechanisms by which neurotrophins allow survival of differentiated neurons within neural circuits. These studies will help identify new signaling pathways that can be exploited to treat neurodegenerative disorders such as Amyotrophic Lateral Sclerosis.

References:

• Rubin JB. Kung AS, Klein RL, Chan JA, Sung YP, Schmidt K, Kieran MW, Luster AD, Segal RA. (2003). A small molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. PNAS; 100 (23): 13513-8.
• Heerssen HM, Pazyra MP, Segal RA. (2004). Dynein motors transport activated Trk to promote neuronal survival. Nat.Neurosci: 7 (6): 596-604.
• Choi Y, Borghesani PR, Chan JA, Segal RA. Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci. 2005 Nov 9;25(45):10437-45.
• Zhou PC, Porcionnato MP, Pilapil MP, Chen YC, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME. Segal RA. (2007) Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron in press.