During embryonic development multipotent precursor cells become restricted to specific cell lineages, undergo differentiation, and form synaptic connections to their appropriate targets. My laboratory is interested in understanding how embryonic precursor cells respond to local environmental cues during the development of the mammalian nervous system. We have focused on two developmental stages in the rat peripheral nervous system: the restriction of neural precursor cells to specific neuronal lineages and the development and function of synaptic connections.

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It has been proposed that sympathetic neurons and the enteric neurons of the mammalian gut are derived from common embryonic progenitors. We are testing the hypothesis that early rat sympathetic and enteric neuroblasts are developmentally plastic in terms of their final cell fate, and that during development these cells become restricted as a result of interactions with factors in their local embryonic environment. Our approach has been to challenge neuroblasts from these lineages with an environment that promotes differentiation to an alternative lineage. We have developed methods for marking sympathetic and enteric neuroblasts to enable us to identify these cells when cultured in different microenvironments. We have followed the development of these marked neuroblasts in co-cultures containing cells known to promote the development of sympathetic or enteric neurons. We are using mass cultures of dissociated gut cells as our "enteric differentiation environment" and cultures of primary dorsal aorta cells as our "sympathetic differentiation environment". In each case, these cells represent the local environment in which enteric or sympathetic neurons develop. In control experiments, we have demonstrated that the sympathetic environment promotes the development of a sympathetic phenotype, while the gut environment promotes an enteric phenotype. We have now used this system to determine that at early developmental stages both enteric and sympathetic neuroblasts are plastic in regard to their final neuronal cell fate. This plasticity is lost in both of these lineage by late developmental stages. The loss of the potential to respond to alternative lineage cues is not linked to initial neuronal differentiation of the precursor cells but takes place during the period of neuronal maturation. Current investigations are directed at understanding the nature of the local environmental cues that control lineage restriction in the periphery. These studies will provide an understanding of the relationship between differentiation and lineage restriction, and define the molecular mechanisms leading to developmental restriction.

Another focus of the laboratory is to understand the role of target-derived trophic factors on the formation and function of synapses between sympathetic neurons and heart tissue. Nerve growth factor (NGF), acting through the trkA receptor tyrosine kinase, plays a role in the development and survival sympathetic neurons. We have recently demonstrated that NGF also acts to acutely potentiate synaptic transmission between sympathetic neurons and cardiac myocytes in culture. Cardiac myocytes beat spontaneously in culture. If a synaptic connection exists between a neuron and a beating myocyte, electrical stimulation of the neuron results in synaptic transmission between the neuron and the myocyte and an increase in myocyte beat rate. This culture system is analogous to the situation in the animal where increased sympathetic input to the heart results in an increased heart rate. Using this system, we have demonstrated that, in the presence of NGF, stimulation of a neuron leads to a greater postsynaptic response of a connected myocyte. We have demonstrated that NGF acts presynaptically to mediate the level of synaptic transmission between the neuron and its target. The finding that NGF acutely and reversibly modulates synaptic transmission between sympathetic neurons and myocytes raises the question of how synaptic activity, NGF and NGF receptors interact to lead to long term changes in synaptic function. Ongoing investigations in the laboratory are also addressing the developmental role of NGF in the establishment of peripheral synaptic connections. We have found that NGF acts as one signal in a series of interactions between neurons and myocytes resulting in the development of sympathetic presynaptic machinery.

Selected Publications:

Luther JA, Birren SJ. (2009) Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties. Auton Neurosci. 2009 Nov 17;151(1):46-60. [abstract]

Luther JA, Birren SJ. (2009) p75 and TrkA signaling regulates sympathetic neuronal firing patterns via differential modulation of voltage-gated currents. J Neurosci. 2009 Apr 29;29(17):5411-24. [abstract]

Dore JJ, Dewitt JC, Setty N, Donald MD, Joo E, Chesarone MA, Birren SJ. (2009) Multiple Signaling Pathways Converge to Regulate Bone-Morphogenetic-Protein-Dependent Glial Gene Expression.Dev Neurosci. 2009 Mar 27. [abstract]

Habecker BA, Bilimoria P, Linick C, Gritman K, Lorentz CU, Woodward W, Birren SJ. (2008) Regulation of cardiac innervation and function via the p75 neurotrophin receptor. Auton Neurosci. 2008 Jun;140(1-2):40-8.

Moon JI, Birren SJ. (2008) Target-dependent inhibition of sympathetic neuron growth via modulation of a BMP signaling pathway. Dev Biol. 2008 Mar 15;315(2):404-17.

Lin PY, Hinterneder JM, Rollor SR, Birren SJ. (2007) Non-cell-autonomous regulation of GABAergic neuron development by neurotrophins and the p75 receptor. J Neurosci. 2007 Nov 21;27(47):12787-96.

Slonimsky JD, Mattaliano MD, Moon JI, Griffith LC, Birren SJ. (2006) Role for calcium/calmodulin-dependent protein kinase II in the p75-mediated regulation of sympathetic cholinergic transmission. Proc Natl Acad Sci U S A. 2006 Feb 13. [full text]

Luther JA, Birren SJ. (2006) Nerve growth factor decreases potassium currents and alters repetitive firing in rat sympathetic neurons. J Neurophysiol. 2006 Aug;96(2):946-58. [abstract]

Dore JJ, Crotty KL, Birren SJ. (2005) Inhibition of glial maturation by bone morphogenetic protein 2 in a neural crest-derived cell line. Dev Neurosci., 27:37-48. [full text]

Slonimsky, J.D., Yang, B., Hinterneder, J.M., Nokes, E.B. and Birren, S.J. (2003) BDNF and CNTF regulate cholinergic properties of sympathetic neurons through independent mechanisms. Mol. Cell. Neurosci. 23:648-660 [full text]

Yang B, Slonimsky JD, Birren SJ. (2002) A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor. Nat Neurosci 5:539-545. [abstract in PubMed] [full text in .PDF file]

Bharmal, S, Slonimsky, J.D., Mead, J.N., Sampson, C.P.B., Tolkovsky, A.M, Yang, B., Bargman, R., and Birren, S.J. (2001). Target interactions promote the functional maturation of neurons derived from a sympathetic precursor cell line. Dev. Neurosci. 23:153-164. [abstract]

Worley, D.S., Pisano J.M., Choi, E.D., Walus, L., Hession, C.A., Cate, R.L., Sanicola, M., and Birren, S.J. (2000). Developmental regulation of GDNF response and receptor expression in the enteric nervous system. Development. 127:4383-93 [abstract]

Pisano JM, Colon-Hastings F, Birren S.J. (2000). Postmigratory enteric and sympathetic neural precursors share common, developmentally regulated, responses to BMP2. Dev Biol. 227:1-11. [abstract]

Lockhart, S.T., Mead, J.N., Pisano, J.M., Slonimsky, J.D., and Birren, S.J. (2000). Nerve growth factor collaborates with myocyte-derived factors to promote development of presynaptic sites in cultured sympathetic neurons. J. Neurobiol. 42:460-476. [abstract]

Pisano, J.M. and Birren, S.J. (1999). Restriction of developmental potential during divergence of the enteric and sympathetic neuronal lineages. Development. 126:2855-2868. [abstract] [full text] (requires journal subscription)

Lockhart, S.T., Turrigiano, G.G., and Birren, S.J. (1997). Nerve growth factor modulates synaptic transmission between sympathetic neurons and cardiac myocytes. J. Neurosci. 17:9573-9582. [abstract] [full text] (requires journal subscription)

 

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Last review: August 8, 2011