Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning

Abstract

Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is important for neuronal development and plasticity and is often dysregulated in psychiatric disorders. Mice mutant for the transcription factor Sp4 have reduced levels of NMDAR subunit 1 (NR1) protein, but not mRNA, and exhibit behavioral and memory deficits (Zhou et al., 2010). In developing cerebellar granule neurons (CGNs), Sp4 controls dendrite patterning (Ramos et al., 2007). Sp4 target genes that regulate dendrite pruning or NR1 levels are not known. Here we report that Sp4 activates transcription of Nervous Wreck 2 (Nwk2; also known as Fchsd1) and, further, that Nwk2, an F-BAR-domain containing protein, mediates Sp4-dependent regulation of dendrite patterning and cell surface expression of NR1. Knockdown of Nwk2 in CGNs increased primary dendrite number, phenocopying Sp4 knockdown, and exogenous expression of Nwk2 in Sp4-depleted neurons rescued dendrite number. We observed that acute Sp4 depletion reduced levels of surface, but not total, NR1, and this was rescued by Nwk2 expression. Furthermore, expression of Nr1 suppressed the increase in dendrite number in Sp4- or Nwk2-depleted neurons. We previously reported that Sp4 protein levels were reduced in cerebellum of subjects with bipolar disorder (BD) (Pinacho et al., 2011). Here we report that Nwk2 mRNA and NR1 protein levels were also reduced in postmortem cerebellum of BD subjects. Our data suggest a role for Sp4-regulated Nwk2 in NMDAR trafficking and identify an Sp4-Nwk2-NMDAR1 pathway that regulates neuronal morphogenesis during development and may be disrupted in bipolar disorder.

Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects

“…Moreover, an increasing body of evidence has suggested that Sp4 transcription factor has a role in complex psychotic disorders through its regulation of a large network of genes, including components of NMDAR signaling pathways (Fuste et al, 2013; Ji et al, 2013; Pinacho et al, 2011; Pinacho et al, 2013; Sun et al, 2015; Zhou et al, 2005). Notably, we also observed reduced SP4 protein abundance without changes in its mRNA expression in the cerebellum of schizophrenia subjects and in peripheral blood mononuclear cells from first-episode psychosis patients (Fuste et al, 2013; Pinacho et al, 2013).…”

Membrane Charge Directs the Outcome of F-BAR Domain Lipid Binding and Autoregulation

“…These activities and interactions define a recycling route by which activated receptors can be removed from signal-permissive early endosomes, downregulating their activities and controlling synaptic growth (Rodal et al, 2011). Mammalian Nwk homologs have been implicated in membrane remodeling and receptor traffic in stereocilia and in cerebellar granule neurons (Cao et al, 2013; Sun et al, 2014). Unraveling these trafficking pathways requires a deeper understanding of the membrane-deforming activities of Nwk.…”

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…The SP4 gene recognizes GC-rich sequences of 'CpG islands' around the promoters of a variety of genes and is neuronally localized (Supp et al, 1996;Zhou et al, 2005). SP4 is therefore highly expressed during neuronal differentiation (Sun et al, 2014;Zhou et al, 2007), and regulates dendritic patterning and neural development during maturation (Ramos et al, 2007;Zhou et al, 2007). Importantly, the SP4 gene was deleted in some patients with schizophrenia (Tam et al, 2010;Zhou et al, 2010), whereas single-nucleotide polymorphisms of SP4 have also been associated with schizophrenia (Zhou et al, 2009), bipolar disorder, and major depressive disorder (Pinacho et al, 2011;Shi et al, 2011;Zhou et al, 2009).…”