Apical dendrites of pyramidal neurons in the neocortex have a stereotypic orientation that is important for neuronal function. Neural recognition molecule Close Homolog of L1 (CHL1) has been shown to regulate oriented growth of apical dendrites in the mouse caudal cortex. Here we show that CHL1 directly associates with NB-3, a member of the F3/contactin family of neural recognition molecules, and enhances its cell surface expression. Similar to CHL1, NB-3 exhibits high-caudal to low-rostral expression in the deep layer neurons of the neocortex. NB-3-deficient mice show abnormal apical dendrite projections of deep layer pyramidal neurons in the visual cortex. Both CHL1 and NB-3 interact with protein tyrosine phosphatase a (PTPa) and regulate its activity. Moreover, deep layer pyramidal neurons of PTPa-deficient mice develop misoriented, even inverted, apical dendrites. We propose a signaling complex in which PTPa mediates CHL1 and NB-3-regulated apical dendrite projection in the developing caudal cortex.

Neural adhesion molecule NB-3 plays an important role in the apical dendrite development of layer V pyramidal neurons in the visual cortex, and receptor-like protein-tyrosine phosphatase ␣ (PTP␣) mediates NB-3 signaling in this process. Here we investigated the role of PTP␣ in regulating cell surface expression of NB-3. We found that cortical neurons from PTP␣ knock-out mice exhibited a lower level of NB-3 at the cell surface. When expressed in COS1 cells, NB-3 was enriched in the Golgi apparatus with a low level of cell surface expression. However, co-expression of PTP␣ increased the cell surface distribution of NB-3. Further analysis showed that PTP␣ facilitated Golgi exit of NB-3 and stabilized NB-3 protein at the cell surface by preventing its release from the plasma membrane. The extracellular region of PTP␣ but not its catalytic activity is necessary for its effect on NB-3 expression. Thus, the PTP␣-mediated increase of NB-3 level at the cell surface represents a novel function of PTP␣ in NB-3 signaling in neural development. Protein-tyrosine phosphatase ␣ (PTP␣)4 is a receptor-like protein phosphatase with two cytoplasmic protein-tyrosine phosphatase domains (D1 and D2) and a relatively short and highly glycosylated extracellular domain. PTP␣ is widely expressed in many tissues, including the nervous system, the immune system, and many cancer cells (1). As an essential component of several Src family kinase-dependent signaling pathways, PTP␣ acts in conjunction with ligand-activated receptors, ion channels, and cell adhesion molecules to dephosphorylate and activate Src family kinases (2-9). In this manner PTP␣ affects many fundamental cellular processes, including mitosis (10 -12), migration (13-15), proliferation (16,17), and transformation and tumorigenesis (5, 18). PTP␣ is particularly highly expressed in the brain, and it affects many aspects of neural development and function, such as neurite outgrowth, neuronal differentiation and migration, ion channel activity, oligodendrocyte differentiation and myelination, hippocampal long term potentiation, and spatial memory (2, 6, 8, 9, 13, 19 -24). In particular, PTP␣ mediates neural adhesion molecules NB-3 and Close Homolog of L1 (CHL1) signaling in developing layer V pyramidal neurons in the caudal cortex and is required for correct apical dendrite projection of these neurons in vivo (25).Dendrite development is an important process in neural development. Apical dendrites of cortical pyramidal neurons, the major sites for these neurons to receive excitatory inputs, exhibit a stereotypic orientation toward the pial surface. Neural adhesion molecules NB-3 and CHL1 regulate apical dendrite orientation in the mouse visual cortex (25,26). NB-3 belongs to the contactin subgroup of the immunoglobulin (Ig) superfamily (27). Like other contactin family members, NB-3 contains six Ig-like domains and four fibronectin type III (FNIII) repeats. It lacks a transmembrane and intracellular domain and is anchored at the cell surface via a glycosylphosphatidylinositol (G...