although recent evidence indicates that axonal regeneration and neural pathway reconstruction can occur following central nervous system ( cns ) injury , brain and spinal axons can not rapidly or effectively traverse the site of injury . glial scar formation , in particular , hinders axonal regeneration and cns self - repair . consequently , trauma , ischemia and degenerative disease can result in permanent and severe disability . microtubule - associated protein 1b ( map1b ) is one of the first maps expressed in neuroblasts , and is essential for axonal development and regeneration . it can induce cytoskeletal rearrangements by regulating actin and microtubule dynamics , and promote axonal growth , development , branching and regeneration . moreover , it plays an important role in axon guidance and neuronal migration . a variety of signaling molecules are associated with axonal development and regeneration or axonal guidance , such as netrins , neurotrophic factor and wnt , and signaling molecules associated with neuronal migration , such as reelin , modulate map1b function . however , the signaling pathways that regulate map1b function and the underlying molecular mechanisms remain poorly understood . here , we review recent advances in our understanding of map1b function and regulation . an appreciation of the underlying molecular mechanisms should help researchers in their efforts to promote cns repair and axonal regeneration , and lead to effective methods for neurological functional recovery following cns injury . the precursor polypeptide undergoes proteolytic processing to generate the c - terminal - derived light chain and the n - terminal - derived heavy chain . the c - terminal product is a small protein , called map1b light chain 1 , which contains a microtubule and actin binding domain and can regulate interactions between microtubules and microfilaments . the map1b heavy chain contains a microtubule - binding domain and mediates binding of map1b light chain 1 to microtubules . cueille et al found that the map1b heavy chain binds actin and regulates interactions between microtubules and actin . this indicates that map1b can regulate microtubule stability , interactions between microtubules and actin , and axonal extension . map1b heavy chain is mainly involved in axonal longitudinal growth , microtubule stability and local actin dynamics , while map1b light chain 1 may enhance growth cone dynamics by providing nodes for f - actin assembly . phosphorylated map1b is categorized as type i or type ii , i.e. p1-map1b or p2-map1b . the balance between map1b and phosphorylated map1b p1-map1b is generated by phosphorylation by various protein kinases , such as glycogen synthase kinase 3 ( gsk3 ) and cyclin - dependent kinase 5 . p1-map1b mainly aggregates in distal axons and growth cones during neural development to respond to extracellular factors . p1-map1b gradually disappears following axonal maturation , and is used as a marker of axonal growth . proteomics shows that map1b accumulates in the growth cone during axonal development to a greater extent than in elongating axons . in addition , inhibiting map1b function significantly slows axonal development , indicating the importance of map1b in axonogenesis and elongation . cultured neurons from a mouse line deficient in map1b showed that axonal elongation was significantly reduced , indicating inhibition of map1b function can partly suppress axonal growth , consistent with another study showing that other maps also promote axonogenesis . knockout of map1b and map2 or map1b and tau significantly impairs axonal sprouting , but knockout of map2 and tau does not , suggesting that although the functions of the various map family members partly overlap , map2 and tau can not replace map1b in axonal development . the quantity of map1b in neurons is tightly controlled , because low or high map1b levels can result in delayed axonal sprouting , pathological axonogenesis and reduced axonal growth . map1b contains microtubule and actin binding domains ; thus , it can regulate microtubule and actin stability . neuronal cultures from map1b knockout mice exhibit delayed neuronal migration and suppressed neurite elongation , but microtubule extension into growth cones is increased . inhibiting map1b phosphorylation increases the size of growth cones and leads to shortened and thickened axons . immunodepletion of map1b significantly increases the sensitivity of microtubules in the distal axon and growth cone to nocodazole - induced depolymerization , indicating that map1b increases the ability of microtubules to resist depolymerization . this may be related to the ability of map1b to induce microtubule protein acetylation and reduce levels of tyrosinated microtubules , thereby increasing microtubule stability . in addition , map1b has been shown to regulate growth cone guidance and inhibit branching of regenerating axons , but kuo et al demonstrated that axonal branching is increased following map1b depletion . map1b in distal axons and growth cones can interact with tubulin - tyrosine ligase to promote microtubule tyrosination and regulate microtubule dynamics , but map1b phosphorylation does not affect this interaction . map1b can not induce microtubule tyrosination because the tubulin - tyrosine ligase binding site is shielded . map1b in axon terminals and growth cones promotes microtubule tyrosination , thereby regulating microtubule dynamics and stimulating axonal elongation . in contrast , map1b at other sites along the axon primarily stabilizes microtubules and prevents microtubule depolymerization . previous studies have shown that axons are thickened and shortened , and growth cone extension is increased following inhibition of map1b phosphorylation , while deletion of map1b or increasing the map1b / p - map1b ratio increases microtubule stability . moreover , phosphorylated map1b mainly regulates microtubule dynamics in growth cones and growing axons , indicating that it contributes to microtubule stability and dynamics and plays an important role in regulating microtubule stability , because extensive promotion or inhibition of microtubule stability can affect axonal growth and development . microtubules and the associated map1b extend into growth cones , and microtubules within the growth cone can bind actin . this indirectly indicates that map1b binds actin , thereby regulating the interaction between microtubules and actin . phosphorylated map1b can enhance growth cone motility by regulating actin dynamics in the growth cone . in the initial stage of axonogenesis , phosphorylated map1b is at very low levels , but its levels increase with axonal development and elongation . p1-map1b levels are highest in the growth cone , where it binds axonal terminal microtubules . there , it primarily regulates axonal elongation by modulating microtubule dynamics and interactions between microtubules and actin 35 , 38 ] . nerve growth factor interacts with tropomyosin - related tyrosine kinase to activate the mitogen - activated protein kinase / extracellular regulated kinase pathway , which in turn indirectly stimulates gsk3 phosphorylation through other kinases . other proteins , such as dystroglycan , can also interact with map1b and modulate gsk3-mediated map1b phosphorylation . gsk3-mediated map1b phosphorylation results in microtubule sensitivity to depolymerization and increases the quantity of unstable microtubules , thereby promoting axonal elongation . reduced map1b phosphorylation by inhibiting gsk3 activity through the wnt pathway thickens and shortens axons , and enlarges growth cones and stabilizes microtubules . nerve growth factor activates phosphatidylinositol-3 kinase ( pi3k ) and induces gsk3 phosphorylation at ser-9 , which blocks the ability of gsk3 to activate primed substrate , i.e. substrate that is pre - phosphorylated at certain residues . two types of gsk3 phosphorylation sites , primed and non - primed , are found in map1b . therefore , nerve growth factor can negatively regulate p1-map1b following pi3k activation , i.e. nerve growth factor can regulate p1-map1b levels through the mapk and pi3k pathways . in pc12 cells , nerve growth factor activates neuron - specific p35 by activating the mapk - erk1/2 pathway . subsequently , p35 binds cdk5 to form an active complex that phosphorylates map1b to generate p1-map1b . cdk5 is distributed throughout the cytoplasm and axons , while p35 is only found in axon terminals and growth cones . therefore , cdk5 can only be activated in axon terminals and growth cones , possibly contributing to the large amount of p1-map1b at these sites , which plays crucial roles in microtubule dynamics , axonal elongation and growth cone guidance . the c - jun n - terminal kinase ( jnk ) phosphorylates a variety of cytoskeletal proteins , including map1b and map2 . blocking the jnk pathway reduces map1b phosphorylation , resulting in axonal degeneration and cytoskeletal defects . tanner et al reported that map1b may also regulate interactions between the cytoskeleton and the cell membrane , and between the cytoskeleton and the extracellular matrix or adhesion molecules . during synaptogenesis at the end stage of axonal development , map1b promotes axonal development through three pathways : ( 1 ) map1b promotes membrane skeleton assembly through interactions with f - actin ; ( 2 ) map1b interacts with phospholipids ; ( 3 ) map1b crosses the plasma membrane and functions as a type i membrane protein . at least one form of map1b located at presynaptic and postsynaptic regions has been demonstrated to interact with cell membranes and synapsin , contributing to synapse formation and function in the later stages of axonal development . the injured corticospinal tract forms new connections with spinal neurons , which aids neurological functional recovery to an extent . mrna and protein expression are significantly increased in cortical infarct foci and surrounding regions , promoting sensory and motor functional recovery . map1b can regulate interactions between microtubules and actin , and microtubules aggregate only in the presence of map1b . cueille et al proposed that interactions between microtubules and actin play important roles not only in neurogenesis and differentiation , but also in axonal regeneration and neuronal connectivity in adults , indicating that map1b promotes axonal regeneration by regulating interactions between microtubules and actin and that high expression of map1b in the cns contributes to neural plasticity . similar to axonal development , the ability of map1b to promote axonal regeneration and neuronal connectivity are highly correlated with map1b phosphorylation . following traumatic brain injury , map1b and phosphorylated map1b exhibit a brief period of high expression in the hippocampus , cortex and thalamus , which has been demonstrated to associate with cytoskeletal protein stability . soares et al reported that levels of phosphorylated map1b rapidly increase in newly generated axons near the spinal cord lesion , and neurons highly express phosphorylated map1b in the spinal cord following injury and periphery nerve injury , which promotes axonal reconstruction . p1-map1b and p2-map1b have distinct functions during axonal regeneration . upregulated p1-map1b expression is associated with axonal regeneration , and upregulated p2-map1b expression is associated with synaptic plasticity after injury . map1b and phosphorylated map1b the jnk pathway has been shown to play an important role in axonal regeneration in jnk gene - deficient mice . phosphorylated jnk aggregates in distal axons during axonal regeneration , and promotes microtubule elongation and axonal sprouting by inducing map1b phosphorylation . following spinal cord injury , jnk pathway activity is increased , which promotes axonal sprouting and regeneration associated with map1b phosphorylation . similar to processes in axonal development , the jnk pathway can catalyze map1b phosphorylation during axonal regeneration . however , the correlation between cns axonal regeneration and development , and the precise roles of map1b and phosphorylated map1b in cns axonal generation and functional recovery require further investigation . during axonal growth , the growth cone is responsible for signal perception and directing axon elongation . actin is regarded as the main skeletal component for growth cone genesis and guidance , but studies have demonstrated that dynamic microtubules surrounding the growth cone play a major role in regulating growth cone guidance . the growth cone responds to the axon guidance factor netrin-1 and other extracellular guidance cues by transducing these signals into changes in microtubule structure , and microtubule stability and growth is the structural basis of axon guidance . buck et al demonstrated that changes in local microtubular stability , growth and polymerization / depolymerization mediate growth cone navigation . the regulation of microtubule dynamics and microtubule and actin interactions allows map1b to mediate growth cone migration , which is related to the netrin signaling pathway . netrin-1 is an important guidance molecule and induces intracellular signaling cascades by binding receptor deleted in colorectal cancer . netrin-1 can enhance map1b expression through cdk5 and gsk3 , and it can deactivate phosphorylated map1b in growth cones , resulting in impaired growth cone guidance . p1-map1b mediates axon elongation to facilitate the formation of neural connections with target tissues or organs . therefore , map1b and p1-map1b maintain microtubule dynamic balance and regulate subcellular distribution to promote axonal growth and guide migration . map1b can also guide neuronal migration . similar to its role in axon guidance , map1b regulates neuronal migration , and the dynamic balance between map1b and p1-map1b regulates neuronal morphology and promotes neuronal directional movement . map1b gene defects result in delayed neuronal migration , ectopic localization , cortical plate defects and abnormal cns development , indicating that the protein is involved in axonal elongation and neuronal migration , which is associated with actin and microtubule dynamics . during neuronal migration cns neuronal migration depends on the dynamic balance between stable and dynamic microtubules , which is mediated by map1b and p1-map1b . map1b can induce dynein , a protein involved in cell migration , to bind lissencephaly - related protein 1 . deletion of map1b can attenuate their interaction , indicating the important role of map1b in neuronal migration . bouquet et al proposed that map1b exerted similar effects through related mechanisms in different types of cells ( figure 1 ) . the main pathways that regulate map1b phosphorylation during neuronal migration . the reelin pathway modulates map1b function to promote neuronal migration . pi3k has been reported to inhibit gsk3 activity and negatively regulate map1b phosphorylation , thereby influencing neuronal migration . map1b : microtubule - associated protein 1b ; gsk3 : glycogen synthase kinase 3 ; jnk : c - jun n - terminal kinase . reelin may promote nervous system development through phosphorylation of map1b and other maps ( such as lissencephaly - related protein 1 ) . reelin is an extracellular matrix protein that regulates neuronal migration and localization in the cns by modulating map1b function . reelin induces disabled 1 phosphorylation through very low density lipoprotein receptor and apolipoprotein receptor 2 . the pi3k pathway regulates p1-map1b levels by inhibiting gsk3 activity to maintain microtubular instability and promote neuronal migration . netrin-1 stimulates map1b phosphorylation by activating gsk3 and cdk5 to produce p1-map1b , which regulates interaction of microtubules and actin , to mediate neuronal migration . in addition , netrin-1 interacts with its receptor , deleted in colorectal cancer , to activate the rho gtpase rac1 . thus , the netrin-1-rac1-gsk3/cdk5-map1b pathway may be an effective means of controlling neuronal migration , but this idea requires verification . kawauchi et al reported that the t - cell lymphoma invasion and metastasis 1 ( tiam1)-rac1-jnk pathway plays an important role in neuronal migration . tiam1 activates rac1 and stimulates neuronal migration by regulating actin cytoskeleton dynamics , and jnk regulates microtubule dynamics by stimulating map1b phosphorylation to control neuronal migration . the effects of cdk5 , gsk3 and jnk on microtubule dynamics must be tightly regulated to maintain the balance between microtubule stability and instability . otherwise , cytoskeletal dynamics would be impaired , perturbing neuronal migration . therefore , reelin and netrin-1 play important roles in neuronal migration through effects on map1b . they regulate microtubule stability and dynamics , maintain balance between microtubules and actin , and control their interaction to promote axonal growth , connectivity , and regeneration post - injury . further studies are needed on map1b to investigate treatments to rapidly and effectively ameliorate cns injury and improve the quality of patient 's life .
in this review , we discuss the role of microtubule - associated protein 1b ( map1b ) and its phosphorylation in axonal development and regeneration in the central nervous system . 
 map1b exhibits similar functions during axonal development and regeneration . 
 map1b and phosphorylated map1b in neurons and axons maintain a dynamic balance between cytoskeletal components , and regulate the stability and interaction of microtubules and actin to promote axonal growth , neural connectivity and regeneration in the central nervous system .