Following the migration of the axonal growth cone to its target area, the initial axo-dendritic contact needs to be transformed into a functional synapse. This multi-step process relies on overlapping but distinct combinations of molecules that confer synaptic identity. Slitrk molecules are transmembrane proteins that are highly expressed in the central nervous system. We found that two members of the Slitrk family, Slitrk1 and Slitrk2, can regulate synapse formation between hippocampal neurons. Slitrk1 is enriched in postsynaptic fractions and is localized to excitatory synapses. Overexpression of Slitrk1 and Slitrk2 in hippocampal neurons increased the number of synaptic contacts on these neurons. Furthermore, decreased expression of Slitrk1 in hippocampal neurons led to a reduction in the number of excitatory, but not inhibitory, synapses formed in hippocampal neuron cultures. In addition, we demonstrate that different leucine rich repeat domains of the extracellular region of Slitrk1 are necessary to mediate interactions with Slitrk binding partners of the LAR receptor protein tyrosine phosphatase family, and to promote dimerization of Slitrk1. Altogether, our results demonstrate that Slitrk family proteins regulate synapse formation.

The accessory olfactory system controls social and sexual behaviours in mice, both of which are critical for their survival. Vomeronasal sensory neuron (VSN) axons form synapses with mitral cell dendrites in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor (VR) converge into multiple glomeruli within spatially conserved regions of the AOB. Here, we have examined the role of the cell adhesion molecule Kirrel2 in the formation of glomeruli within the AOB. We find that Kirrel2 expression is dispensable for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons into the anterior and posterior regions of the AOB, but is necessary for glomeruli formation. Specific ablation of Kirrel2 expression in VSN axons results in the disorganization of the glomerular layer of the posterior AOB and in the formation of fewer and larger glomeruli. Furthermore, simultaneous ablation of Kirrel2 and Kirrel3 expression leads to a loss of morphologically identifiable glomeruli in the AOB, reduced excitatory synapse numbers, and larger presynaptic terminals. Taken together, our results demonstrate that Kirrel2 and Kirrel3 are essential for the formation of glomeruli and suggest they contribute to synaptogenesis in the AOB.

Mechanisms that regulate cellular differentiation in developing embryos are maintained across multiple physiological systems, including the nervous system where neurons and glia are generated. The olfactory epithelium, which arises from the olfactory pit, is a stratified tissue in which the stepwise generation of neurons and support cells can easily be assessed and followed during embryogenesis and throughout adulthood. During olfactory epithelium morphogenesis, progenitor cells respond to factors that control their proliferation, survival, and differentiation in order to generate olfactory receptor neurons that detect odorants in the environment and glia-like sustentacular cells. The tight temporal regulation of expression of proneural genes in dividing progenitor cells, including Mash-1, Neurogenin-1, and NeuroD1, plays a central role in the production of olfactory receptor neurons. Multiple factors that either positively or negatively affect the generation of olfactory receptor neurons have been identified and shown to impinge on the transcriptional regulatory network in dividing progenitor cells. Several growth factors, such as FGF-8, act to promote neurogenesis by ensuring survival of progenitor cells that will give rise to olfactory receptor neurons. In contrast, other molecules, including members of the large TGF-β family of proteins, have negative impacts on neurogenesis by restricting progenitor cell proliferation and stalling their differentiation. Since recent reviews have focused on neurogenesis in the regenerating adult olfactory epithelium, this review describes neurogenesis at embryonic stages of olfactory epithelium development and summarizes our current understanding of how both cell intrinsic and extrinsic factors control this process.