在毛皮动物生产中毛发是最重要的一项指标，作为毛发形成和发育的器官，毛囊在毛发生长过程中起到了决定性作用。毛囊发育异常会导致动物出现脱毛、被毛无光泽、毛皮手感粗硬等问题。不同信号传导通路以协同或拮抗等作用调控毛囊发育及动物体内各种生理活动稳定运行[1]。研究表明，表皮活性β-catenin诱导毛乳头细胞群生成并调节其活性与大小[2-3]，同时表皮活性β-catenin是毛乳头细胞诱导毛囊生成所必须的[4-5]。局部β-catenin的过表达会导致毛囊纤维化和毛囊周期性紊乱[6-7]。而Wnt/β-catenin信号通路作为最关键的生物学调节系统之一，因其复杂的蛋白质作用网络及其在早期动物胚胎发育、组织器官形成、组织再生及创伤后愈合等生理活动中的调控作用，已成为当今生命科学研究的热点和难点。大量研究表明，在毛囊的生长发育及毛囊周期调控中，Wnt/β-catenin信号通路起到重要作用[8-10]，但目前并不清楚Wnt/β-catenin信号通路调控毛囊发育的分子机制。本文论述了Wnt/β-catenin信号通路构成和核内激活，综述了Wnt/β-catenin信号通路对毛囊形态发生和再生的调控作用，以及成骨细胞抑制因子(Dkk)和部分营养物质通过Wnt/β-catenin信号通路对毛囊发育的调控作用，为哺乳动物毛囊发育过程中Wnt/β-catenin信号通路的调控作用研究提供借鉴。
1 Wnt/β-catenin信号通路组成及核内激活 1.1 Wnt/β-catenin信号通路组成Wnt/β-catenin信号通路是在早期胚胎发育中调控细胞增殖、细胞极性和细胞凋亡的基本机制之一，高度保守，普遍存在于多细胞真核生物中[1]。而β-catenin是整个Wnt/β-catenin信号通路的核心，通路的激活或抑制主要由胞质内的β-catenin含量决定[11]。无Wnt配体时，在破坏复合物的降解作用下，细胞质中β-catenin含量降低，通路活性受到抑制。破坏复合物由轴蛋白(Axin)、结肠腺瘤性息肉蛋白(adenomatous polyposis coli，APC)、酪蛋白激酶1(casein kinase 1，CK1)和糖原合成酶激酶-3(glycogen synthase kinase-3，GSK-3)构成。CK1和GSK-3依次对β-catenin氨基末端区域的磷酸化是β-catenin降解的开始，泛素连接酶(ubiquitin ligase，E3)上关键组分β-传导重复相容蛋白(β-transducin repeats-containing proteins，β-Trcp)能识别并泛素化降解磷酸化后的β-catenin[12-13]。持续的胞质内β-catenin降解作用阻止了β-catenin入核，Wnt靶基因转录活性由于转导素样分裂增强子(transducin like enhancer of split, TLE)及组蛋白去乙酰化酶(histone deacetylases, HDAC)对与DNA结合的T细胞因子(T cell factor，TCF)/淋巴增强因子(lymphoid enhancer factor，LEF)转录因子的抑制作用显著降低。当Wnt配体与其受体卷曲蛋白(frizzled, Fz或Fzd)及其辅助受体低密度脂蛋白受体相关蛋白6(low-density lipoprotein receptor-related protein 6，LRP6)/低密度脂蛋白受体相关蛋白5(low-density lipoprotein receptor-related protein 5，LRP5)结合时，Wnt/β-catenin信号通路激活。Wnt-Fz-LRP6复合物的形成以及蓬乱蛋白(dishevelled，Dvl)的聚集导致了LRP6的磷酸化和活化，与此同时破坏复合物向Fz聚集。这一系列的生化反应就使破坏复合物对β-catenin的磷酸化作用失效，β-catenin累积入核，与TCF/LEF形成复合物并激活靶基因表达[14]。
1.2 Wnt/β-catenin信号通路的核内激活β-catenin在胞核内的聚集是Wnt/β-catenin信号通路核内激活的关键。Wnt-Fz-LRP6复合物的形成使胞质内β-catenin稳定存在。而叉头盒蛋白M1(forkhead box protein M1，FoxM1)、胰岛素受体底物-1(insulin receptor substrate-1，IRS-1)、B细胞淋巴瘤9(B-cell lymphoma 9，BCL9)以及粘蛋白1(mucin-1)等蛋白可与β-catenin结合并促其入核；同时Ran结合蛋白3(ran binding protein 3，RanBP3)、CHibby、APC、Axin、GSK3等蛋白通过与β-catenin的相互作用使β-catenin从胞核内脱离出来；近期研究发现，葡萄糖诱导降解蛋白8同源物(glucose-induced degradation protein 8 homolog，Gid8)可通过促进β-catenin在胞核内滞留进而提高胞核内β-catenin水平[15]。当胞质内的β-catenin大量入核，胞核内β-catenin解除TCF/LEF的转录抑制，激活转录活性继而靶基因表达[16-17]。目前主流的转录抑制解除观点是入核的β-catenin可直接与转录因子TCF/LEF结合，使靶基因的转录抑制状态转变为激活状态[18-20]。TCF/LEF转录因子家族的4个成员(TCF-1、TCF-3、TCF-4和LEF-1)是β-catenin依赖性核内激活的主要调节因子[20]。早有研究确定了LEF-1促进毛囊发育和毛发生长的重要作用，同时LEF-1可与β-catenin协同以调控毛囊周期[21]。与此同时，转录因子间也存在相互作用，如TCF-1可与LEF-1协同作用促进胸腺细胞成熟，同时TCF-1抑制LEF-1表达进而抑制早期胸腺细胞发育中的恶性转化[22]。在人乳腺癌上的研究认为，β-catenin与TCF7l1结合后通过降低其染色质占有率来促使TCF7l1失活降解，继而β-catenin与TCF7l1相互作用解除转录抑制[23-24]，但这种在癌变中的抑制解除模式可能并不存在于Wnt/β-catenin调控毛囊发育的过程中。
2 Wnt/β-catenin信号通路对毛囊发育的调控作用 2.1 Wnt/β-catenin对毛囊形态发生的调控作用毛囊的形态发生起始于胚胎早期，大致可分为诱导、器官发生以及细胞分化3个阶段[25]。毛囊形态发生受Wnt、Hedgehog、Notch、BMP等多信号通路间相互作用调控[26-29]。Wnt/β-catenin信号通路是诱导阶段最重要的通路之一，研究表明，在真皮上皮、基板上皮、真皮浓缩物以及基板成纤维细胞中均可检测到β-catenin表达[30-33]。间充质和背覆上皮通过分泌信号分子相互作用调控毛囊形态发生[34]，真皮乳头(dermal papillae，DP)在间充质信号传导中心与上覆上皮相互作用以调控毛囊形态发生[35]，近期有研究表明，真皮乳头细胞可通过其外泌体调控毛囊形态发生过程[36-39]。间充质内Wnt/β-catenin信号通路的激活促使被覆上皮增厚形成基板是诱导毛囊形态发生的开始[34]。基板形成后，基板中成纤维细胞生长因子20(fibroblast growth factor，FGF20)表达上调调控真皮浓缩物的生成[35]。研究表明，上皮Wnt配体分泌导致的真皮浓缩物中的Wnt/β-catenin信号通路激活是毛囊形成所必须的，持续激活的Wnt/β-catenin会导致真皮增厚，基板和真皮浓缩物的过度增大导致毛囊过早分化[26]。同时FGF20的表达受Wnt/β-catenin信号通路与EDA/EDAR/NF-kB信号通路调控[35]。研究发现，Wnt/β-catenin信号通路与EDA/EDAR/NF-κB信号通路是最早对毛囊形态发生起调控作用的两条通路[32, 36]。在EDA/EDAR/NF-κB信号激活之前，已检测到局部Wnt/β-catenin活性以及β-catenin表达上调，同时在特异性抑制外胚层Wnt/β-catenin信号通路活性的前提下，过表达EDA或激活EDAR不能激活EDA/EDAR/NF-κB信号，同时抑制了胚胎期初级毛囊的发育[33]。基板增殖、真皮浓缩物的生成以及角质形成细胞的大量增殖标志着毛囊器官发生的开始[34]。早有研究表明，Wnt/β-catenin可通过LEF-1介导的上皮型钙黏附蛋白下调促进Shh表达[40]，而上皮Shh信号通路激活可促进真皮乳头细胞成熟，并通过Noggin维持其功能特性[38]。毛囊分化是毛囊各组分诸如毛干、内根鞘以及外根鞘在多种信号分子的调控作用下发育并形成完整毛囊的过程[25]。毛囊细胞分化过程受基础间充质内由Wnt5a和FoxN1介导的Notch-CSl通路的调控[41]，而wnt5a可促进FoxN1表达[25]。研究表明，FoxN1在角质形成细胞和毛囊的分化中发挥重要的调控作用[42], 特异性FoxN1信号传导可将色素从黑色素细胞传导至毛囊角质形成细胞[43]。Wnt/β-catenin信号通路在毛囊细胞分化中主要起促进毛干生长的作用，研究表明，牡荆素复合物1(vitexin compound 1，VB-1)可通过提高人真皮乳头细胞Wnt/β-catenin信号通路活性促进毛发生长[44]；分泌的卷曲相关蛋白1(secreted frizzled related protein 1, SFRP1)可通过抑制人毛囊球部wnt配体分泌抑制Wnt/β-catenin信号通路活性，特异性抑制SFRP1活性可促进毛干增长并提高毛干角蛋白表达[45]；临床研究认为，低水平激光可促进毛发生长，试验以655 nm红光和LED照射，可提高毛干伸长率以及人毛囊器官培养过程中的毛干过度生长，同时提高毛发基质中β-catenin、p-GSK3以及LEF-1蛋白表达水平[46]。
2.2 Wnt/β-catenin对毛囊再生的调控作用毛囊再生即毛囊由静止期重新进入到生长期[47]。活化BMP信号通路诱导毛囊发育进入退行期[25]，抑制剂处理抑制毛囊由生长期至退行期可检测到BMP-4的表达抑制[48]。对BMP信号通路的抑制以及随后Wnt/β-catenin信号通路的激活是毛囊再生的开始[49]。毛囊干细胞在毛囊再生中发挥重要作用[50-52]，真皮乳头与毛囊干细胞的干扰以及Wnt/β-catenin与BMP抑制因子之间的相互作用激活毛囊干细胞活性，同时促进毛囊由静止期向毛发生长初期的转变[49, 53-57]。Wnt5a以及LEF-1的表达上调促进核因子1-C(nuclear factor 1-C，NF1-C)表达上调，而NF1-C通过上调TGFβ-1和抑制细胞周期蛋白依赖性激酶抑制剂1a(cyclin-dependent kinase inhibitor 1a, p21)促进角质形成细胞增殖并启动毛发生长初期诱导[58-59]。近期研究表明，真皮乳头中的Hoxc具有控制毛囊再生的作用，差异微环境Hoxc通过Wnt/β-catenin通路调控毛囊干细胞活性，进而调控不同部位毛囊再生模式[60]。
2.3 成骨细胞抑制因子(Dkk)对毛囊发育的调控作用研究表明，Dkk可抑制Wnt/β-catenin信号通路活性，使毛囊发育退行[61]。由Dkk基因编码的Dkk分泌蛋白，其蛋白家族由Dkk-1、Dkk-2、Dkk-3、Dkk-4构成[62]。通路活性可被Dkk-1和Dkk-4直接抑制，Dkk-2在不同的细胞环境中分别扮演激动剂或抑制剂的角色。目前的观点认为，Dkk-1和Dkk-4实现对Wnt/β-catenin信号通路的调控作用是因为Dkk-1和Dkk-4可直接提高与LRP5/6的亲和力并与之结合，同时抑制Wnt-Fz-LRP6复合体的相互作用，使入核β-catenin减少，从而抑制通路活性[63]。跨膜蛋白kremens1(Krm1)和kremens2(Krm2)作为Dkk受体，能与Dkk-1配合以阻断通路信号传导，其机制是Krm2可与Dkk-1以及LRP6结合形成三元复合物，诱导快速的内吞作用并使Wnt受体LRP6从质膜上脱落，进而抑制通路活性。同时，在不同的细胞环境下，Dkk-2既可以作为LRP6的激动剂又可作为其拮抗剂，而krm2在其由激动剂向抑制剂的转变中起到了开关作用[64-65]。有研究表明，Dkk-1对毛囊周期的调控作用可使毛囊由生长期进入退行期，使毛发变短[66]。当胞质内Dkk-1促凋亡蛋白(BCL2-associated X protein，Bax)表达增加时，可明显检测到胞质内Bax浓度升高，导致其与B淋巴细胞瘤基因-2(B-cell lymphoma-2，Bcl-2)比例升高，继而导致在毛囊发育及周期调控中起到重要作用的外根鞘角质形成细胞和毛囊球部细胞凋亡[67-68]。然而，在毛发生长初期和中期，大多数Wnt/β-catenin信号通路经典信号分子如LEF-1等的表达要强于休止期[69]。而Dkk-1作为Wnt/β-catenin信号通路的抑制剂具有使毛囊由生长期进入退行期的作用，推测Dkk-1不仅可以作为Wnt/β-catenin信号通路抑制剂，同时也是毛囊发育及毛囊周期调控的调节剂。
2.4 其他调节因子对毛囊发育的调控作用随着人们对毛囊发育的研究深入，越来越多对毛囊发育起调控作用的调节因子被发现。在哺乳动物皮肤中可以检测到wnt3a、wnt4、wnt5a、wnt6、wnt7a、wnt10a、wnt10b、wnt11、wnt16，但目前仍不确定其中部分wnt配体在毛囊发育中的作用[70]。研究认为，B淋巴细胞诱导的成熟蛋白1(B-lymphocyte-induced maturation protein 1，Blimp1)有促进毛囊发育的作用。研究表明，小鼠成纤维细胞中Blimp1消融会抑制毛囊形态发生和生长，而稳定的β-catenin过表达又可以覆盖Blimp1突变体的毛囊发育缺陷[71]。在药物性抑制GSK3后，可清晰检测到Blimp1上调[72]。这就说明Blimp1作为Wnt/β-catenin通路的下游效应分子对毛囊发育的调控作用。去泛素化蛋白酶7(ubiquitin-specific-processing protease 7，USP7)可直接与β-catenin N末端相互作用，调控β-catenin去泛素化进而实现对Wnt/β-catenin信号通路的正向调控[73]。表皮中活性YES相关蛋白(yes-associated protein，YAP)可激活β-catenin，通过Wnt/β-catenin信号通路调控毛囊发育[74-75]。另有研究表明，背板胶质乙酰酯酶(notum)可特异性去除Wnt蛋白上的棕榈油酸修饰，使wnt蛋白去乙酰化，从而实现对Wnt/β-catenin信号通路的抑制作用[76-77]。另外，硬骨素(sclerostin，SOST)可能通过与LRP5/LRP6的结合，破坏由Wnt配体诱导的FZD与LRP6结合，激活破坏复合物对β-catenin的降解作用，进而抑制通路活性[78]。
2.5 营养物质通过Wnt/β-catenin信号通路对毛囊发育的调控作用诸多营养物质如氨基酸等可通过Wnt/β-catenin信号通路实现对毛囊发育的调控作用。早有研究确定了wnt10b对促进毛囊上皮细胞分化的重要作用[79]。饲粮中适宜蛋氨酸添加水平能促进獭兔背部皮肤中wnt10b表达，同时提高獭兔皮肤毛囊密度[80]。对水貂和獭兔的研究发现，培养基中添加适宜浓度的蛋氨酸能显著提高毛囊生长长度，同时适宜蛋氨酸水平可以促进水貂毛乳头细胞增殖，而毛乳头细胞作为毛囊最重要的组成细胞之一，对毛囊发育至关重要[80-81]。黄岑苷可提高Wnt/β-catenin信号通路活性，促进毛囊发育，其可能的作用机制是通过刺激wnt配体分泌，作用靶点位于破坏复合物的上游[82]。天冬氨酸-丝氨酸-丝氨酸重复多肽能促进wnt10b、lef-1和c-myc基因表达，可能以上调信号分子表达水平的方式提高通路活性来促进毛囊发育，对脱毛处理小鼠的研究表明，天冬氨酸-丝氨酸-丝氨酸重复多肽能显著促进毛囊进入生长期，其可能的作用机制是通过激活PI3K/Akt信号通路，使GSK-3磷酸化失活，使胞质内β-catenin稳定存在，进而维持Wnt/β-catenin信号通路活性，促进毛囊发育[83]。维生素D受体及其配体有促进角质形成细胞分化和增殖的作用，研究表明，人和小鼠的维生素D受体异常会导致严重的毛囊周期性再生受损，但其具体的分子作用机制仍需要进一步的研究证实[84]。
毛囊是哺乳动物皮肤上的重要附属结构，是控制被毛生长最重要的器官之一，毛囊发育情况决定了动物被毛的品质和产量[85]。正常情况下，哺乳动物毛囊发育包括胚胎期的毛囊形态发生以及出生后的毛囊周期性变化，毛囊周期分为生长期(anagen)、退行期(catagen)、静止期(telogen)，毛囊再生是指毛囊由静止期重新进入生长期，多种调节因子调控毛囊形态发生和周期性变化[25, 86-87]。甚至调节性T细胞也在毛囊再生以及毛囊的周期调控中起作用[88]。在Wnt/β-catenin信号通路这一复杂的蛋白质作用网络中，任何一种调节因子的异常表达都会影响机体正常发育。大量研究表明，在Wnt/β-catenin信号通路的调控作用下动物胚胎发育以及胚胎干细胞的增殖分化才能正常运行。同样，哺乳动物毛囊发育以及毛囊周期的调控也离不开Wnt/β-catenin信号通路的作用[24, 89]。
3 结论与展望尽管人们对毛囊发育中Wnt/β-catenin信号通路的调控作用及其研究不断深入，但仍有诸多问题需要进一步研究，如组成毛囊的不同细胞中激活Wnt/β-catenin信号通路的wnt配体及其受体、不同抑制剂分子在构成毛囊的多种细胞中的抑制作用是否相同，以及在毛囊发育不同阶段Wnt/β-catenin信号通路活性调节以及不同调节范围机制研究。可以确定，Wnt信号转导是毛囊形态发生和毛囊再生必需的，同时Wnt信号在整个毛囊发育过程中的多样性调控作用是多信号通路共同作用的结果。目前，Wnt/β-catenin信号通路中关键调节因子的作用研究主要是过表达和以抑制剂处理两种方式，目前的抑制剂处理往往是上游抑制，抑制掉整条通路活性后很难发现通路中真正起调控作用调节因子，同时Wnt/β-catenin信号通路中关键调节因子又可能是其他信号通路调节因子，因此，采用过表达以及上游抑制剂处理所得到的结果有可能并不十分严谨。并且由于Wnt/β-catenin信号通路在动物机体发育、维持机体正常生理活动以及创伤修复方面不可取代的作用，应当充分考虑过表达和抑制剂处理所带来的副作用，更应该探索新的研究方法。未来的研究应更多地关注不同发育阶段和组织类型所需的多信号通路交叉互作，以及wnt受体和配体在各皮肤层中的特异性表达。
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