Transcription factor Sp4 regulates dendritic patterning during cerebellar maturation

Abstract

Integration of inputs by a neuron depends on dendritic arborization patterns. In mammals, the genetic programs that regulate dynamic remodeling of dendrites during development and in response to activity are incompletely understood. Here we report that knockdown of the transcription factor Sp4 led to an increased number of highly branched dendrites during maturation of cerebellar granule neurons in dissociated cultures and in cerebellar cortex. Time-course analysis revealed that depletion of Sp4 led to persistent generation of dendritic branches and a failure in resorption of transient dendrites. Depolarization induced a reduction in the number of dendrites, and knockdown of Sp4 blocked depolarization-induced remodeling. Furthermore, overexpression of Sp4 wild type, but not a mutant lacking the DNA-binding domain, was sufficient to promote dendritic pruning in nondepolarizing conditions. These findings indicate that the transcription factor Sp4 controls dendritic patterning during cerebellar development by limiting branch formation and promoting activitydependent pruning.branching ͉ dendrite ͉ depolarization ͉ pruning ͉ neuron T he nervous system is a complex and 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 dendritic patterning correlate with severe neurodevelopmental disorders (1-3). Although proper dendritic arborizations are crucial for correct function of the nervous system, the genetic programs that govern dendritic morphology in mammals remain poorly described. Dendritic development is a highly dynamic process that involves many events, including neurite outgrowth, branching, stabilization, and pruning of dendrites (4-6). There is a delicate balance between addition and elimination of neuronal projections (7,8). During development, transient overproduction of branched dendrites appears in most neurons, after which some neurites are eliminated, whereas other neurites are stabilized to achieve the mature pattern (9-11). Recent studies have described intracellular signaling pathways that operate locally to regulate cytoskeletal elements important for branch formation or elimination (12)(13)(14).Extrinsic factors are coordinated with cell-intrinsic, gene expression programs to determine dendritic morphology. Genetic studies in Drosophila and Caenorhabditis elegans have identified transcription factors that regulate diverse aspects of dendritic morphology (15-18). Transcriptional control of the fine balance between formation and elimination of processes is illustrated by the finding that, in Drosophila, the homeodomain protein, Cut, promotes branching, whereas the BTB/POZ Zinc finger transcription, Abrupt, limits branch formation (18,19). In mammals, the transcriptional regulators CREB, NeuroD, and CREST have been identified to promote dendritic growth and branching (20-23). Transcriptional regulators that balance these activities to restrict dendritic branchin...

Class I Histone Deacetylase-mediated Repression of the Proximal Promoter of the Activity-regulated Cytoskeleton-associated Protein Gene Regulates Its Response to Brain-derived Neurotrophic Factor

“…Among the SP family transcription factors, SP4 is predominantly expressed in neuronal cells (36) and contributes to the transcriptional regulation of neuronal genes, such as neurotrophin-3 (Nt-3) (22). Previous studies also reported that SP4 was involved in neuronal functions such as dendritic patterning in the cerebellum (37), development of the hippocampal dentate gyrus (38), and sensorimotor gating and memory (39). Therefore, the SP4-mediated transcriptional regulation of Arc may be involved in the regulation of several types of physiological functions in the brain.…”

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

“…One could theorize that this reduced breakpoint stems from lower NMDAR expression in these mice, but this deficit was not remediated by GlyT-1 inhibition (Figure 4a), unlike that seen for attention (Figure 3). Considering the importance of Sp4 expression during neurodevelopment (Ramos et al, 2007;Zhou et al, 2007), (Figure 5a). This deficit was driven by a reduced likelihood of staying at the target side after being rewarded at that sidehence reduced reward sensitivity (Figure 5c).…”

“…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).…”

PIASx Is a MEF2 SUMO E3 Ligase That Promotes Postsynaptic Dendritic Morphogenesis

“…Two-dimensional reconstruction of Z-series images was then performed using a maximum brightness projection algorithm (Volocity imaging software). Images of transfected granule neurons were analyzed using SPOT software for dendritic length and number of primary and secondary dendrites as described previously (Gaudilliere et al, 2004;Shalizi et al, 2006;Ramos et al, 2007).…”