laboratory of
developmental neurobiology
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Owen M. Rennert, MD,
Acting Chief The goal of the Laboratory of Developmental
Neurobiology (LDN) is to understand the molecular and cellular mechanisms
underlying regulation of the development and function of the nervous system.
Major topics of interest include the mechanisms of processing, intracellular
trafficking, and secretion of neuropeptides and hormones; the molecular
machinery of secretory vesicle biogenesis and the presynaptic release
process; circadian biology with emphasis on the pineal gland and synthesis of
melatonin; and the coupling between action potentials, neurotransmitters,
neurohormones, neurotrophic factors, and regulation of gene expression. Peng Loh’s group, the Section on Cellular Neurobiology, studies intracellular protein
trafficking and granule biogenesis in neuroendocrine and exocrine systems.
The group recently uncovered the molecular basis for the intracellular
missorting of mutant proinsulins found in hyperproinsulinemia patients and
demonstrated a major defect in zymogen secretory granule formation and
maturation in the exocrine pancreas of a mouse model of Smith-Lemli-Opitz
syndrome. The section showed the importance of carboxypeptidase E in a mouse
lacking this enzyme, not only for neuropeptide processing and trafficking but
also in the early development of the nervous system. To identify genes expressed at elevated levels
at night and genes selectively expressed in the pineal gland, David Klein’s group, the Section on Neuroendocrinology, has
applied microarray technology to the analysis of control of pineal function.
The section also initiated a global analysis of rhythmic and pineal-specific
genes, with the intention of identifying common critical regulatory elements.
In addition, the section led an NICHD initiative to develop a commercial
microarray tool for analyzing gene expression in the zebrafish. Led by Andres Buonanno, the Section on Molecular Neurobiology
found that distinct neuregulins, a family of growth and differentiation factors
that regulate the expression of glutamate neurotransmitter receptors and that
were recently implicated in schizophrenia, are expressed in diverse neuronal
populations during development and are differentially targeted to either axon
terminals or dendrites, suggesting that these related factors have
nonoverlapping functions in brain. Philip Nelson’s group, the Section on Neurobiology, studies activity-dependent synaptic
plasticity during development. Both pre- and post-synaptic mechanisms are
involved in the Hebbian response to synapse activation that is captured in
the multicompartment tissue culture model of the neuromuscular junction
developed by the section. An antagonistic interaction between protein kinase
A and C regulates synaptic stability, in particular the loss or retention of
the acetylcholine receptor (AChR). PKA stabilizes and PKC destabilizes the
receptor. The section also demonstrated antagonistic effects of kinase action
on the presynaptic transmitter release and showed that glia-derived
neurotrophic factor (GDNF) increases the stability of the AChR while
minimally affecting the synthesis or membrane insertion of the receptor. |