Different spatiotemporal expression of DOC2 genes in the developing rat brain argues for an additional, nonsynaptic role of DOC2B in early development

Abstract

DOC2A and DOC2B are two homologous genes implicated in synaptic vesicle exocytosis. Their complementary, nonoverlapping expression patterns in adult rat brain suggest that they exert similar functions in different neurons. We have analysed the expression pattern of the two genes in the developing rat brain by in situ hybridization. Unexpectedly, we found no parallel expression of the two genes during development. DOC2B mRNA was highly expressed as early as embryonic day 12 (E12) throughout the neuroepithelium, long before synaptic transmission is functional, and the expression remained abundant from E12 onwards. In contrast, faint expression of DOC2A transcripts was first detected at E17 in ventral brain areas, and it extended gradually to other brain structures in the sequence of their ontology, i.e. structures that had formed first also expressed DOC2A first. At postnatal day 3, both genes were highly expressed throughout the brain. This overlapping expression diverged to the complementary distribution of the adult brain. The temporal and spatial differences in expression point to a functional divergence between these homologous genes during brain development: the pattern of DOC2A is consistent with its proposed synaptic function, whereas that of DOC2B suggests an additional, nonsynaptic role in proliferating cells.

Doc2 Is a Ca2+ Sensor Required for Asynchronous Neurotransmitter Release

“…However, Doc2β was not detected in our cultures by immunoblot analysis using purified Doc2β as a standard (Figure 4B). These findings are consistent with a report indicating that Doc2α is highly expressed in adult neurons (after day 5) whereas Doc2β expression declines during neuronal maturation (Korteweg et al, 2000). …”

Localizing Genes to Cerebellar Layers by Classifying ISH Images

“…Doc2 proteins act as sensors and trigger spontaneous neurotransmitter release in the adult mice Purkinje cells [28]. Doc2b has also been suggested to be involved in embryonic neural development [29]. The fact that Doc2b is only switched on during late postnatal development in the cerebellum is congruent with the fact that the cerebellum becomes developed and functional only after birth, and suggests that this gene plays a role in Purkinje layer development and function.…”

Doc2b Ca2+-binding site mutants act as a gain of function at rest and loss of function during neuronal activity

“…Unlike Doc2a and –b, the third isoform does not have functionally conserved C 2 domains. Doc2a is mainly expressed in the adult brain while Doc2b is more widely expressed in the nervous system and various neuroendocrine tissues (Verhage et al, 1997; Korteweg et al, 2000). Both Doc2a and –b contribute to spontaneous release as shown in knockout and knock-down models (Groffen et al, 2010; Pang et al, 2011).…”