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.
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.
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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
Habecker BA, Anderson ME, Birren SJ, Fukuda K, Herring N, Hoover DB, Kanazawa H, Paterson DJ, Ripplinger CM. Molecular and cellular neurocardiology: Development, cellular and molecular adaptations to heart disease. J Physiol. 2016 Apr 6. doi: 10.1113/JP271840.
Rosado M, Barber CF, Berciu C, Feldman S, Birren SJ, Nicastro D, Goode BL. Critical roles for multiple formins during cardiac myofibril development and repair. Mol Biol Cell. 2014 Mar;25(6):811-27.
Birren SJ, Marder E. Neuroscience. Plasticity in the neurotransmitter repertoire. Science. 2013 Apr 26;340(6131):436-7.
Luther JA, Enes J, Birren SJ. Neurotrophins regulate cholinergic synaptic transmission in cultured rat sympathetic neurons through a p75-dependent mechanism. J Neurophysiol. 2013 Jan;109(2):485-96.
Neseliler S, Narayanan D, Fortis-Santiago Y, Katz DB, Birren SJ. Genetically induced cholinergic hyper-innervation enhances taste learning. Front Syst Neurosci. 2011;5:97.
Luther JA, Birren SJ.
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.
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.
Dore JJ, Dewitt JC, Setty N, Donald MD, Joo E, Chesarone MA, Birren SJ. Multiple Signaling Pathways Converge to Regulate Bone-Morphogenetic-Protein-Dependent Glial Gene Expression. Dev Neurosci. 2009;31(6):473-86.
Habecker BA, Bilimoria P, Linick C, Gritman K, Lorentz CU, Woodward W, Birren SJ. Regulation of cardiac innervation and function via the p75 neurotrophin receptor. Auton Neurosci. 2008 Jun;140(1-2):40-8.
Moon JI, Birren SJ. 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. 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. 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 21;103(8):2915-9.
Luther JA, Birren SJ. Nerve growth factor decreases potassium currents and alters repetitive firing in rat sympathetic neurons. J Neurophysiol. 2006 Aug;96(2):946-58.
Dore JJ, Crotty KL, Birren SJ. Inhibition of glial
maturation by bone morphogenetic protein 2 in a neural crest-derived
cell line. Dev Neurosci. 27:37-48.
Slonimsky, J.D., Yang, B., Hinterneder, J.M., Nokes, E.B.
and Birren, S.J. BDNF and CNTF regulate cholinergic
properties of sympathetic neurons through independent mechanisms. Mol. Cell. Neurosci. 23:648-660.
Yang B, Slonimsky JD, Birren SJ. A rapid switch
in sympathetic neurotransmitter release properties mediated
by the p75 receptor. Nat Neurosci 5:539-545.
Bharmal, S, Slonimsky, J.D., Mead, J.N., Sampson, C.P.B.,
Tolkovsky, A.M, Yang, B., Bargman, R., and Birren, S.J.
Target interactions promote the functional maturation
of neurons derived from a sympathetic precursor cell line. Dev. Neurosci. 23:153-164.
Worley, D.S., Pisano J.M., Choi, E.D., Walus, L., Hession,
C.A., Cate, R.L., Sanicola, M., and Birren, S.J.
Developmental regulation of GDNF response and receptor expression
in the enteric nervous system. Development. 127:4383-93.
Pisano JM, Colon-Hastings F, Birren S.J. Postmigratory
enteric and sympathetic neural precursors share common,
developmentally regulated, responses to BMP2. Dev Biol.
Lockhart, S.T., Mead, J.N., Pisano, J.M., Slonimsky, J.D.,
and Birren, S.J. Nerve growth factor collaborates
with myocyte-derived factors to promote development of presynaptic
sites in cultured sympathetic neurons. J. Neurobiol. 42:460-476.
Pisano, J.M. and Birren, S.J. Restriction of developmental
potential during divergence of the enteric and sympathetic
neuronal lineages. Development. 126:2855-2868.
Lockhart, S.T., Turrigiano, G.G., and Birren, S.J.
Nerve growth factor modulates synaptic transmission between
sympathetic neurons and cardiac myocytes. J. Neurosci. 17:9573-9582.
Last review: April 22, 2016