Glutamate is a major neurotransmitter that regulates dendritic growth, and glutamatergic transmission convergence with Ca²⁺ signalling plays a key role in dendritic differentiation. Based on pharmacology and structural homology, the Glutamate receptors are grouped into four distinct classes, including the AMPA receptors (GluA1–GluA4), the kainate receptors (GluK1–GluK5), the NMDA receptors (GluN1, GluN2A–GluN2D, GluN3A, and GluN3B), and the δ receptors (GluD1 and GluD2) (Traynelis et al., 2010). Among these classes, the AMPAR-type glutamate receptor (AMPAR) mediates the fastest excitatory synaptic transmission in the brain. Studies investigating the role of glutamate and its receptors in dendritic growth are summarised in Table 1. The efficacy of AMPARs in enhancing dendritic growth depends on the overexpressed subunit editing site and splice variant. Regarding the editing variants, the overexpression of the Ca²⁺-permeable AMPAR subunit containing the unedited (Q) variant was reported to enhance dendritic growth (Inglis et al., 2002; Jeong et al., 2006; Prithviraj et al., 2008; Hamad et al., 2011). On the other hand, the overexpression of the edited Ca²⁺-impermeable variant (R) frequently did not affect dendritic growth (Inglis et al., 2002; Prithviraj et al., 2008; Hamad et al., 2011) (Figure 2). The presence of the edited variant (R) in heteromeric AMPARs renders the channel impermeable to Ca²⁺ and influences channel kinetics and single-channel conductance, whereas the Ca²⁺-permeable variant (Q) renders the channel permeable to Ca2+ (Burnashev et al., 1992). Thus, the Ca²⁺ permeability of the overexpressed subunit is a determining factor in promoting dendrite growth. Splice variants of AMPARs can also control dendritic growth. All four AMPAR subunits occur in two spliced versions, named flip-and-flop. The flip-flop change occurs in the proximity of the ligand-binding domain in the extracellular loop (Sommer et al., 1990). In neurons, flip variants are usually predominant in early developmental stages and are replaced by flop variants in adulthood (Monyer et al., 1991). The flip variants have slower desensitisation time than the flop variant, keeping the channel open longer, and thereby allowing more Ca²⁺ influx into the cell. Expectedly, overexpression of the AMPAR subunits GluA1, GluA2, and GluA3 harbouring the flip variant improved dendritic growth (Inglis et al., 2002; Jeong et al., 2006; Prithviraj et al., 2008; Hamad et al., 2011), while overexpression of the flop variant did not affect dendritic growth in neocortical neurons (Hamad et al., 2011). On the other hand, the overexpression of AMPARs GluA1 and GluA2 C-terminal domains in optic tectal neurons reduced dendritic growth (Haas et al., 2006). However, in P28, the overexpression of the GluA1 subunit did not alter the dendritic length (Jeong et al., 2006). Generally, blocking glutamate receptors in rat neocortical organotypic cultures reduced the dendritic growth of these neurons (Baker et al., 1997). Furthermore, the stimulation with the positive allosteric modulators of AMPARs (ampakines) increased the dendritic growth of hippocampal pyramidal neurons in adult rats (Lauterborn et al., 2016). Although chronic treatment with ampakines did not disturb basic synaptic physiology, it positively affected long-term potentiation. Taken together, these studies suggest that AMPARs play a key role in dendritic development and such effect relies on these receptors editing and splice variants. Generally, the Ca²⁺ permeability of AMPARs is a key factor for promoting dendritic growth.

The glutamate kainate receptors (KARs) have also been involved in dendritic growth. Overexpression of the GluK1 kainate subunit promoted inhibitory interneuron dendritic growth, while overexpression of the GluK2 kainate receptor promotes dendritic growth of excitatory pyramidal cells in the neocortex (Jack et al., 2019). The glutamate receptors NMDA type are also involved in dendritic development. In vivo, injection of NMDAR antagonists MK-801 or APV reduced dendritic growth of spinal cord motoneurons (Kalb, 1994). Furthermore, pharmacological antagonising of the GluN2B but not the GluN2A receptor reduced the basal dendrites of neocortical pyramidal cells (Gonda et al., 2020). On the other hand, a single-cell knockout of the glutamate receptor GluN2B in hippocampal granule cells and cortical spiny stellate cells did not alter the dendritic size of these cells (Espinosa et al., 2009). A reduction in dendritic growth has also been reported in glutamate receptor GluN2A knockout hippocampal neurons (Kannangara et al., 2014). Furthermore, the barrelette neurons in the principal trigeminal nucleus had an increased dendritic size in GluNR1 knockout mice (Lee et al., 2005). Blocking NMDARs with APV reduced dendritic length and branching of optic tectal neurons (Rajan and Cline, 1998) and spinal cord motoneurons (Inglis et al., 1998). Overexpression of the NMDARs subunit GluN3B increased dendritic complexity in spinal cord culture (Prithviraj and Inglis, 2008), and overexpression of the GluN2B mutant caused a decrease in dendritic length in neocortical neurons (Sceniak et al., 2019). These studies suggest a role for NMDARs in shaping dendritic trees.

How do glutamate receptors regulate dendritic growth? Generally, glutamate receptors regulate gene expression in neurons by activating various intracellular signalling cascades that phosphorylate transcription factors within the nucleus (Figure 2). On the other hand, it has been reported that glutamate can induce elongation of dendritic protrusions through group I mGluRs within minutes, suggesting that glutamate-induced dendritic growth is often way too rapid to be mediated by slow transcriptional events (Cruz-Martín et al., 2012). However, the exact mechanism by which glutamate induces rapid dendritic growth through group I mGluRs is unknown. One of the best-characterized signal cascades for glutamate-mediated growth regulatory process is the mitogen-activated protein kinase (MAPK) (Wang et al., 2007). MAPK is usually activated following sustained plasma membrane depolarisation, which triggers Ca²⁺ entry to the cell through glutamate receptors. Activity-dependent activation of the MAPK pathway in hippocampal neurons has been shown to elicit stable dendritic protrusion of new filopodia (Wu et al., 2001). Furthermore, the MAPK pathway is important for Ca²⁺ influx-mediated dendritic growth in neocortical neurons (Redmond et al., 2002). The Ca²⁺ permeable ionotropic glutamate receptor activates MAPKs through a signalling route involving the Ca²⁺-sensitive Ras-guanine nucleotide releasing factor, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), and phosphoinositide 3-kinase.

For the NMDARs, the activation of NMDARs triggers Ca²⁺ influx to neurons. Ca²⁺ influx to the cell activates Ca²⁺-dependent kinases to increase ERK phosphorylation (Figure 2). Among these kinases, the CaMKII was identified as a main Ca²⁺-sensitive kinase at the postsynaptic site. Protein kinase C (PKC) and phosphatidylinositol (phosphoinositide) 3-kinase (PI3-kinase) are also other candidate kinases that have been involved in NMDAR-mediated ERK phosphorylation. The high affinity of the calmodulin-binding sequence in PI3-kinase facilitates the association of calmodulin with PI3-kinase. Furthermore, ERK phosphorylation has been implemented in gene regulation. Interestingly, the phosphorylated form of ERK can regulate c-AMP response element binding protein (CREB). There is a strong connection between Ca²⁺ permeable glutamate receptor activation and CREB phosphorylation (Shaywitz and Greenberg, 1999; West et al., 2002). Activation of ERK through Ca²⁺ permeability of glutamate receptors has been shown to increase CREB phosphorylation (Mao et al., 2004). One of the targeted growth-promoting genes of CREB is the BDNF. Interestingly, in cortical neurons, Ca²⁺ influx triggers phosphorylation of CREB, which, by binding to a critical Ca²⁺ response element (CRE) within the BDNF gene, activates BDNF transcription (Tao et al., 1998). Mutation of BDNF CRE, an adjacent novel regulatory element, and a blockade of CREB function resulted in a dramatic loss of BDNF transcription (Tao et al., 1998). For the AMPARs, signalling for dendritic growth looks like the NMDARs. The AMPARs can induce MAPK/ERK phosphorylation (Wang et al., 2004). It has been shown that CaMKII and PI3-kinase are the two kinases that connect a pathway between AMPARs and ERK (Perkinton et al., 1999). Another mechanism by which AMPARs regulate dendrite growth is mediated through RasGRFs, which can form a complex with Ca²⁺-permeable AMPARs and subsequently guarantee a quick response of RasGRFs to Ca²⁺ signals derived from AMPARs to activate Ras-ERK (Tian and Feig, 2006). It is also important to mention that AMPARs have been coupled with p38 signaling, which could represent a determinant mechanism to decide whether nerve cells survive or die (Rivera-Cervantes et al., 2004). Kainate receptor-mediated Ca²⁺ influx has also been shown to trigger ERK phosphorylation in striatal neurons, and the active ERK1/2 cascade activates the downstream transcription factor CREB to participate in the regulation of gene expression (Mao et al., 2004). Taken together, these studies suggested that glutamate receptors ability to induce dendritic growth relies on Ca²⁺ permeability of the receptor and the subsequent increase in intracellular Ca²⁺, which triggers a dendritic growth-promoting signal cascade.

The trafficking of glutamate receptors is involved in dendritic growth. The discovery of the transmembrane AMPA receptor regulatory proteins (TARPs) paved the way to understand how AMPARs traffic to the plasma membrane and how the function of AMPARs is modulated (Straub and Tomita, 2012). By increasing trafficking and modulating the function of AMPARs, TARPS has also been implicated in dendritic growth (Hamad et al., 2014). In summary, overexpression of type I TARPs γ-2, γ-3, and γ-8, known to enhance AMPAR trafficking and insertion of AMPARs into the synaptic membrane, promoted dendritic growth (Figure 2). On the other hand, the overexpression of the TARP γ-4 subunit reduced dendritic growth (Hamad et al., 2014), possibly because it slows the channel opening and closing rates of AMPARs (Pierce and Niu, 2019). Type II TARPs γ-5 and γ-7 (also called non-TARPs), which potentiate the function of AMPARs but do not participate in the trafficking of AMPARs, did not affect the dendritic growth of neocortical neurons (Hamad et al., 2014). Interestingly, the TARP subunits, which increase the trafficking and insertion of new AMPAR subunits in the plasma membrane had elicited dendritic growth, whereas the TARP subunits, which only potentiate the existing receptors, did not affect dendritic growth. Furthermore, overexpression of the kainate receptor auxiliary subunit NETO1 but not NETO2 has been shown to promote dendritic growth of inhibitory interneurons (Jack et al., 2019). Furthermore, in neurons of the dorsal root ganglion, NETO2 plays a crucial and dynamic role in neurite outgrowth during early development and adulthood (Vernon and Swanson, 2017). Thus, these studies suggest that enhancing the AMPARs or kainate receptor density on the plasma membrane could also be another mechanism by which neurons regulate their dendritic growth.

Metabotropic glutamate receptors are also involved in dendrite growth (Figure 2). For instance, in group I metabotropic glutamate receptor 5 (mGluR5) knockout mice, dendritic growth of neocortical spiny stellate neurons was increased (Ballester-Rosado et al., 2010). On the other side, the activation of the metabotropic glutamate receptor mGluR1 decreased cerebellar Purkinje cells dendritic growth, and it does not require activation of phospholipase C or protein kinase C (Sirzen-Zelenskaya et al., 2006). It has been suggested that mGluR1 and mGluR5 receptor coupling to ERK occurred via mechanisms independent of PI3K activity and intracellular and/or extracellular Ca²⁺ concentration (Thandi et al., 2002). Therefore, it has been shown that these two closely related mGluR receptors utilize different G proteins to cause ERK activation and may recruit different tyrosine kinases to facilitate this response (Thandi et al., 2002).

The GABA excitation/inhibition shift occurs during brain development between the first and second postnatal developmental week (Ben-Ari et al., 2007; Kirmse et al., 2015; Luhmann, 2021). The depolarizing effect of GABA, which occurs only in early development in developing neurons, is due to the expression of the cotransporter NKCC1, which causes an efflux of Cl⁻ ions following the activation of GABA_ARs (Blaesse et al., 2009). Thus, the activation of GABA_ARs in early development depolarises the plasma membrane, leading to Ca²⁺ influx through the voltage-dependent Ca²⁺ channels (VDCCs) (Leinekugel et al., 1997). This will raise intracellular Ca²⁺ levels (Tozuka et al., 2005) and thereby promote dendritic growth (Figure 3). Studies investigating the role of GABA and its receptors in dendritic growth are summarised in Table 1. GABA treatment of rat cortical neurons increased dendritic length and branching (Maric et al., 2001). Furthermore, blocking GABA_ARs with bicuculline decreased dendrite length and branching of hippocampal neurons (Barbin et al., 1993). In cerebellar culture neurons, feeding medium enriched with GABA enhanced dendritic growth and dendritic arborization (Baloyannis et al., 1983). Furthermore, it has been shown that GABA serves as a trophic factor for cerebellar granule cells (CGCs) (Hansen et al., 1984). The effect of GABA on CGCc dendrite growth was induced by Ca²⁺ influx through the activation of L-type VDCCs, as it was prevented by the blocker nifedipine (Borodinsky et al., 2003). Interestingly, GABA-induced dendritic growth of CGCs was mediated by GABA_ARs activation and requires Ca²⁺ influx and subsequent activation of CaMKII and ERK1/2 pathways (Borodinsky et al., 2003). Moreover, the adult hippocampal newly born granule cells dendrites were smaller in the γ2 GABA_ARs heterozygote mice (Ren et al., 2015), as GABA_AR-mediates depolarisation of neurons and activate a Ca²⁺-dependent signalling cascade that promotes the expression of the BDNF gene and BDNF release (Baldelli et al., 2002). Furthermore, depolarising GABA is involved in the phosphorylation of CREB during the second postnatal week of newly generated neurons in the adult hippocampus, and that results in an enhancement of dendritic growth (Jagasia et al., 2009). This occurs because CREB signalling converges onto the BDNF pathway for promoting dendritic growth (Tao et al., 1998). Together, these studies suggest that GABA_AR activation induces Ca²⁺ influx, which triggers the activation of the CaMKII and ERK1/2 pathways and this results in CREB phosphorylation and the subsequent transcription of BDNF to promote dendritic growth (Figure 3). However, this effect is restricted only to early postnatal development when GABA is still excitatory. At the end of the postnatal week, the dendritic growth-prompting action of GABA will reach an end as GABA becomes hyperpolarizing (inhibitory), and that inhibitory action is indispensable for the control of network activity.

The role of GABA_BRs in dendritic growth is still not well-documented. However, some studies have reported an effect of the GABA_BRs on dendrite growth. For example, blocking the GABA_BR in organotypic cultures reduced the dendritic growth of migratory inhibitory GABAergic neurons (López-Bendito et al., 2003). The removal of GABA_BR in utero resulted in smaller dendrites of neocortical pyramidal cells due to disruption of cAMP/LKB1 signalling (Bony et al., 2013). These studies suggest that GABA_BRs are also involved in dendritic growth in early development because, during the GABA_BRs activation, they lack coupling to potassium channels and thus exert a non-hyperpolarizing action.

The neurotransmitter serotonin has also been involved in the dendritic growth process (Figure 4; Table 1). Serotonin application to rat cortical neurons has been shown to inhibit dendritic growth and branching (Sikich et al., 1990). On the other hand, serotonin has been shown to increase dendritic growth and branching of cultured thalamic neurons (Persico et al., 2006). Moreover, in organotypic cultures, cerebellar Purkinje cells dendritic growth was promoted by serotonin through 5-HT1A receptors but inhibited by serotonin through 5-HT2A receptors (Kondoh et al., 2004). However, the inhibition of serotonin synthesis, using DL-P-chlorophenylalanine (PCPA), a reversible inhibitor of 5-HT synthesis, during embryonic developmental stage, reduced dendritic growth of adult cortical pyramidal neurons (Vitalis et al., 2007). Serotonergic receptors mediate the dendritic growth process. Activating the serotonin receptor Htr1A with 8-OH-DPAT increased dendritic length and branching in cultured embryonic thalamic neurons in mice (Persico et al., 2006). Later, activation of Htr1A by 8-OH-DPAT for 7 days did not affect dendritic growth in mouse dorsal raphe nuclei slice cultures (Dudok et al., 2009). Similarly, no morphological changes have been revealed in Htr1A knockout mice (Heisler et al., 1998). In addition, the pharmacological blockade of serotonin receptor 1A (Htr1a) increased hippocampal pyramidal dendritic growth at P35 (Ferreira et al., 2010). The Htr1a activation reduces the cAMP levels by inhibiting adenylyl cyclase and increasing autophosphorylation of CaMKIIα, which restricts dendritic growth. The Htr1B receptor seems not to be involved in dendritic growth since Htr1B knockout mice presented with no morphological abnormality (Saudou et al., 1994). Furthermore, activating the 5-HT1a and 5-HT7 receptors increased the dendritic growth of cultured hippocampal neurons (Rojas et al., 2017). The activation of 5-HT1AR and 5-HT7R promotes the growth of short secondary dendrites and triggers ERK1/2 and AKT phosphorylation through MEK and PI3K activation, respectively. Studies on the Htr2A/C receptor have shown different effects on neurite growth. For example, activation of the Htr2A/C receptor decreases the total dendritic length of cerebellar Purkinje cells (Kondoh et al., 2004). However, activation of the Htr2A/C enhanced dendritic growth of cultured embryonic mouse thalamic neurons in mice (Persico et al., 2006). Among the serotonin receptors, Htr3 is the only ionotropic receptor subtype. The activation of the Htr3 receptor with m-CPBG enhanced the dendritic growth of cultured rat cortical neurons (Vitalis and Parnavelas, 2003). No abnormalities were found in Htr3A knockout mice (Walstab et al., 2010), however, an enhancement of apical dendrite length has been reported in the neocortical neurons of Htr3A knockouts (van der Velden et al., 2012). Therefore, how do serotonin receptors modulate dendritic growth? First of all, as the studies above suggested, serotonin has a different growth action for dendritic growth, and that effect depends on the nature of the receptor (Figure 4). For instance, the Htr1 and Htr5 receptor families are inhibitory. On the other hand, the Htr2, Htr3, Htr4, Htr6, and Htr7 receptor families are excitatory. Furthermore, the stimulation of 5-HT4R with the agonist RS67333 had increased hippocampal neurons dendritic growth (Agrawal et al., 2019) as it upregulates the expression of the neurotrophic factors BDNF, NT-3, NGF as also the TRK-A receptor. Moreover, Htr3 is ionotropic and could depolarize the plasma membrane, resulting in cations influx. The other serotonin receptors are G protein-coupled (GPCR). For example, Htr1, Htr4, Htr5, Htr6, and Htr7 modulate cAMP activity, and by increasing cAMP activity, CREB can be phosphorylated, targeting BDNF transcription. For the Htr3 receptor, serotonin-induced increases in intracellular Ca²⁺, which are mediated by 5-HT (3) receptors and L-type Ca²⁺ channels, and subsequent activation of calmodulin and calcineurin have been shown to enhance NGF-induced neurite outgrowth (Homma et al., 2006). The serotonin receptors activating the G protein have a dendritic growth signalling pathway (Figure 4). For instance, the serotonin receptor Htr1A activation leads to a number of neurotrophic events by activating a series of signal transduction molecules and these effect s has been shown to be mediated through G protein (Fricker et al., 2005). Finally, serotonin has been shown to induce the expression of growth factors, in particular BDNF (Vaidya et al., 1997). Taken together, these studies suggest that serotonin modulate dendritic growth. The action of serotonin depends on the nature of the activated receptor as well as the activated signaling cascade.

Cadherins are transmembrane proteins that mediate cell–cell adhesion. Cadherins play a crucial role in tissue morphogenesis and homeostasis by regulating contact formation and stability. Several cadherin/protocadherins have been implicated in dendrite growth. The studies on the role of cadherins and protocadherins in dendritic growth are summarised in Table 4. For instance, conditionally knocking out the γ-protocadherins (γ-pcdhs) in adult olfactory bulb granule cells decreased dendritic growth (Ledderose et al., 2013), as they control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signalling pathway (Garrett et al., 2012; see also Figure 7). Eliminating Celsr2 seven-pass transmembrane cadherins decreased dendritic growth in neocortical pyramidal cells (Shima et al., 2007; see also Figure 7). The effect of Celsr2 on dendritic growth depends on the activation of CaMKIIβ, which promotes dendritic growth. Furthermore, eliminating Celsr3 seven-pass transmembrane cadherins in neocortical pyramidal neurons increased dendritic growth (Shima et al., 2007). The effect of Celsr3 on dendritic growth depends on calcineurin activation. Furthermore, γ-Pcdhs act locally to promote dendrite arborization via homophilic matching, and that depends on molecular interactions between neurons and between neurons and astrocytes (Molumby et al., 2016). Moreover, retinal amacrine cells (ACs) project primary dendrites into a discrete synaptic layer called the inner plexiform layer and rarely extend processes into other retinal layers. The atypical cadherin Fat3 ensures that ACs develop this unipolar morphology (Deans et al., 2011; see also Figure 7). AC precursors are initially multipolar but lose neurites as they migrate through the neuroblastic layer. In cadherin fat3 mutants, dendritic growth is enhanced (Deans et al., 2011; Krol et al., 2016). These studies suggest that cadherins and protocadherins are critical in dendritic development.

The Eph receptors represent mammals largest known family of receptor tyrosine kinases. These receptors are critical for a variety of normal cellular processes during development. The studies on the role of ephrins in dendritic growth are summarised in Table 4. It has been shown that hippocampal neurons showed a reduced dendritic size in EphB receptor (EphBR) knockout mice (Hoogenraad et al., 2005). A possible explanation is that the extracellular domain of EphBR is involved in the clustering and functional enhancement of NMDA receptor expression, which plays a role in dendritic development (Grunwald et al., 2001). Moreover, cortical pyramidal cells showed increased dendritic size in EphA7 knockout mice compared to wild-type mice (Clifford et al., 2014). Furthermore, the ephrin-B3, a transmembrane ligand for Eph receptors, functions postsynaptically as a receptor to transduce reverse signals into developing dendrites of mouse hippocampal neurons (Figure 7). Both tyrosine phosphorylation-dependent GRB4 SH2/SH3 adaptor-mediated signals and PSD-95-discs large-zona occludens-1 (PDZ) domain-dependent signals are required for inhibition of dendrite branching (Xu et al., 2011). Furthermore, suppressing ankyrin repeat-rich membrane-spanning protein (ARMS) using in utero electroporation reduced cortical neurons dendritic growth, as ankyrin is required for neurotrophin and ephrin receptor-dependent dendrite development (Chen et al., 2012). The PI3K and Akt-mediated signalling pathways are crucial for ARMS-dependent dendrite development (Figure 7). Recently, it has been shown that there is a functional crosstalk of VEGFR2 and ephrinB2 in vivo to control dendritic arborization (Harde et al., 2019). Hippocampal pyramidal cells showed reduced dendritic growth in the vascular endothelial growth factor receptor 2 (VEGFR2) knockout mice (Harde et al., 2019), as VEGF activates the signalling partner of the Src family kinases to promote dendritic growth (Figure 7). Taken together, these studies suggest the role of ephrins in dendritic growth.

Wingless/Wnts are signalling molecules which play a role in dendritic development. WNTs signal through their Frizzled (FZ) receptors to be able to activate the cytoplasmic scaffolding protein Dishevelled (DVL). WNTs can also signal through the tyrosine kinase-related receptor RYK, which interacts with FZ and DVL (Figure 8). Downstream of DVL, the WNT pathway diverges into at least three branches: the canonical or WNT/β-catenin pathway (Figure 8), the planar cell polarity (PCP) pathway and the WNT/Ca²⁺ pathway (Ciani and Salinas, 2005). The studies on the role of Wnts in dendritic growth are summarised in Table 4. Eliminating the Wnt Ryk receptor in dissociated hippocampal and cortical neurons also increased dendritic growth (Lanoue et al., 2017). Ryk is known to signal through the PCP pathway, and the depletion of Ryk expands the dendritic tree. Furthermore, when overexpressed, the Wnt5a-Frizzled4 signalling pathway has increased the dendritic growth of the developing hippocampal neurons. The growth effect of Fzd4 was mediated by the downstream signalling cascade of the distal PDZ-binding motif of Fzd4 (Bian et al., 2015). The elimination of Frizzled-7 (Fz7) reduced the dendritic growth of granule cells (Ferrari et al., 2018). The Fz7 induces the phosphorylation of CaMKIIβ, which mediates dendritic growth. Furthermore, Wnt7b, expressed in the mouse hippocampus, increases dendritic branching in cultured hippocampal neurons through Dishevelled, Rac and JNK (Rosso et al., 2005). Moreover, Wnt-2 increased dendritic growth and branching of primary hippocampal neurons (Wayman et al., 2006). Finally, the non-canonical Wnt pathway induced by Wnt5a is important for the morphological development of olfactory bulb interneurons both in vitro and in vivo (Pino et al., 2011). Together. these studies suggest that the Wnt signalling molecules are important for dendritic development.

Semaphorins comprise a large family of conserved proteins that act as guidance cues and dendritic development and guidance in many organisms. The studies on the role of semaphorins in dendritic growth are summarised in (Table 4). Semaphorin 3A (Sema3A), a class III semaphorin, has been shown to regulate the radial orientation of pyramidal neurons in the developing neocortex (Figure 8). It is implicated in the elaborating second and third-order dendritic branches in pyramidal neurons in the neocortex (Fenstermaker et al., 2004). In Sema3A mutant mice, atypical proximal bifurcation of CA1 pyramidal apical dendrites was increased (Nakamura et al., 2009). The proximal bifurcation of CA1 pyramidal neurons was also increased in the mutant mice of p35, an activator of cyclin-dependent kinase 5 (Cdk5), suggesting that Sema3A may facilitate the initial growth of CA1 apical dendrites via the activation of p35/Cdk5, which may in turn signal hippocampal development (Nakamura et al., 2009). Interestingly, the Sema3A controls cortical development through remote signalling. It has been proposed that retrograde Sema3A signalling regulates the glutamate receptor localization through the trafficking of AMPAR GluA2 along dendrites; this remote signalling may be an alternative mechanism to local adhesive contacts for neural network formation (Goshima et al., 2016). Moreover, the neutralisation of plexin-B1, the semaphorin 4D (Sema4D) receptor, with an antibody resulted in a reduction in the dendritic growth of dissociated neocortical neurons (Saito et al., 2009) since Plexin B1, which is a dual functional GAP for R-Ras and M-Ras, remodels dendrite morphology. Moreover, silencing of semaphorin receptors neuropilins (NRP) 1 or 2 in neural progenitors at the adult mouse dentate gyrus resulted in newly differentiated neurons with shorter dendrites and simpler branching in vivo through the activation of Cdk5-FAK signalling pathway (Ng et al., 2013). Moreover, Sema3A promotes the extension of hippocampal dendrites by a pathway that requires focal adhesion kinase (FAK). The stimulation of dendrite growth and FAK phosphorylation by Sema3A depends on integrin engagement (Schlomann et al., 2009). Moreover, the Sema3A-regulated dendritic development of cortical pyramidal neurons required phosphorylation of collapsin response mediator proteins (CRMP1) by Fyn is an essential step (Kawashima et al., 2021). Furthermore, Sema3A regulates basal pyramidal dendritic length on cortical neurons via Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signalling pathway that specifically controls dendritic morphogenesis (Danelon et al., 2020; see also Figure 8). Moreover, Sema3A signalling during dendritic growth in cerebellar granule neurons requires the PlexinA3/CRMP2 pathway (Jiang et al., 2020, see also Figure 8). Taken together, these studies suggest the role of the Sema3A in modulating dendritic architecture in early development.

Neuregulins are a family of four structurally related proteins making part of the EGF family. These neuregulins have been shown to have multiple functions during the development of the nervous system. Many studies have shown that neuregulins can regulate dendritic development. The studies on the role of neuregulins in dendritic growth are summarised in (Table 4). For instance, in rat retinal cell cultures, when added to cultures of embryonic or neonatal rat retinal cells, neuregulin (rhGGF2) promotes survival and neurite extension from retinal neurons in a dose-dependent manner (Bermingham-McDonogh et al., 1996). Moreover, the neuregulin Ig-NRG plays a crucial role in cerebellar granule cell dendrite outgrowth by increasing the expression of the GABA_AR beta2 subunit (Rieff et al., 1999). Furthermore, it has been shown that the neuregulin NRG-1beta stimulates hippocampal dendrite extension and arborization via a signalling pathway that involves erbB membrane tyrosine kinases (erbB2 and/or erbB4), p42/44 ERK, and PKC (Gerecke et al., 2004; see also Figure 8). Moreover, it has been shown that neuregulin-4 (Nrg4) binds to its receptor ErbB4 and promotes dendritic growth of the striatal medium spiny neurons (Paramo et al., 2019). Indeed, in the motor cortex, the Nrg4 is required to maintain the pyramidal cells soma size (Paramo et al., 2021). Finally, in cortical GABAergic inhibitory interneurons, the neuregulins 1, 2, and 3 promote early dendritic growth in ErbB4-expressing cells (Rahman-Enyart et al., 2020; see also Figure 8). Thus, the neuregulin plays a key role in early dendritic development.