Target Genes of Transcription Factor Sp4 in Neuronal Development.
Abstract: The nervous
system is a well-coordinated network that depends on the formation of proper connections
among diverse types of neurons. Dendritic arborization patterns determine the way a
neuron integrates inputs. Defects in this process are associated with neurodevelopmental
disorders, such as schizophrenia (SZ). N-methyl-D-aspartate (NMDA) neurotransmission
plays an important role in... read moreneuronal plasticity, cognition and memory. Altered NMDA
neurotransmission may underlie the pathophysiology of multiple psychiatric disorders.
Transcription factor (TF) Sp4 controls dendritic patterning during cerebellar
development by limiting branch formation and promoting activity-dependent pruning. Sp4
is associated with multiple neuropsychiatric disorders, such as schizophrenia and
bipolar disorders (BD). Sp4 regulates NMDA receptor 1 (NMDAR1) protein level, as has
been shown by a Sp4 hypomorphic mouse model. However, little is known about the target
genes of Sp4 involved in regulating neuron development and NMDA neurotransmission. We
identified Sp4-regulated genes by comparing global gene expression between wild type and
Sp4 hypomorphic mouse cerebellum. Of the differentially expressed genes, several have
roles in neuron development, and several have altered expression in neuropsychiatric
disorders. In particular, we identified Nervous Wreck 2 (Nwk2) as an activation target
of Sp4 that regulates dendritic patterning and NMDAR protein levels. Nwk2 in mammals is
a homolog of Nwk in Drosophila, which plays a vital role in synapse growth. Nwk2
expression was reduced in Sp4 hypomorphic cerebellum and cerebellar granule neurons
(CGNs). Sp4 localized to the Nwk2 promoter (CGNs). Knockdown of Nwk2 in CGNs produced
increased number of primary dendrites, which phenocopied the effect of Sp4 knockdown on
primary dendrites. Importantly, exogenous expression of Nwk2 in Sp4 depleted CGNs
rescued the morphology of neurons. Furthermore, NMDA receptor protein level was reduced
in Nwk2 knockdown CGNs, which was consistent with the observation of NMDAR1 loss in Sp4
hypomorphic and knockdown CGNs. Overexpression of NMDAR in Sp4 or Nwk2 depleted neurons
rescued the increase in dendrite number. Our studies identify Sp4-Nwk2-NR1 as a new
pathway that contributes to normal neuronal morphogenesis and may be disrupted in
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Genetics.
Advisor: Grace Gill.
Committee: Philip Hinds, Victor Hatini, and Gavin Schnitzler.
Keywords: Biology, and Genetics.read less