发现：uncover; give insight into; Disclosed
调节：control; regulate; mediate
引起，导致，出现、发生：causing; leading to; result in; occur; exhibited
再出现，复发，恢复：recur; eversal; restoration; renovation; rehabilitation; recovery
改变、影响： change; alter; vary; influence; impact; affect; effect
消耗: consuming; cost
不同、区别：may differ between follicle types;
The vibrissal follicle in this respect differs in manyways from the pelage follicle
共同点：a property thus shared by these two inductive mesenchymal tissues
与...相反: in contract of; in contract to; conversely
包括、包含、组成：include; involve; for example; such as; like;contain; consists of;For example, ... Moreover; Composed of; It contains; make up; made of；
comprises a complex assortment of proteins;
divided into six subphases;
被当作，被看作: X is considered as; act as a; consider the hair follilce as anattractive system for studying; considerd to be; recogized tobe; service as; identified as;
ALP is referred as an excellent marker of DPCs
放置，放入..之中，放在与…一起：placed free-floating in serum -free medium;
Placed with the connective tissue sheath
方法，方式：by means of
支持: in favor of
维持，保持：retained; remains; maintain
发生，生长： give rise to; appears to be established during; establish
... 在场的情况下： in the presence of; major pathways involved...
... 缺乏的情况下：in theabsence of; lack of
In the hair follicle, telomerase is only weaklyexpressed in the area of the bulge and strongly expressed in thelower bulb cells
Stains intensely for versican
It is found that telomerase expression ceases withthe onset of catagen, a change that may reflect no more than the dramaticdecline in cell proliferation associated with this phase of the cycle
表达上调；下调：upregulated by; downregulated by; influenceby molecules
角色：player; role; candidate;agent; mode; plays a key role
必要的，重要的角色：the imperative role of ; The important role of; undoubtedly play; a critical role in; be Essential to
必不可少的：indispensable to; an important component of; play a pivotalrole in; play an active role in; play a significant role in;
its role is thought to serve predominately as asupport for the
重要功能：the most obvious function of; mostimportant function
方式、治疗方式：method; way; type; mode; application forX therapy;
a promising approach;
a novel therapeutic target for gene therapy
an eddective approach
a potential innovative strategy for
a novel function and mechanism of
be considered as an agent for clinical application.
regarding microRNAs’ therapeutic potential and accessibility of hair folliclesfor gene therapy can be considered as good candidates for a new revolutionizedgeneration of treatments.
offering new mechanistic insight
准确的病因、机制:precise aetiology and pathogenesis: exact mechanisms
许多的，各种各样的：multiple; diversity;various; several; a number of
显著地：significantly; dramatic; signally; observably; markedly; memorably
主要的、关键的：paramount for; key components for; a pivotal regulator of; a novel candidate for directaction on; important target; plays a key role; plays a crucial role in ; a novel mode for
联系、关系: correlation; is linked to; relate to; in correlation with;
相关: associated with;relevant to
主要的、关键的：paramount for; key components for; a pivotal regulator of; a novel candidate for directaction on
新的模式，治疗方法：a novelmode for;
its potential application for skin whitening therapy;
a promising approach;
provide new promising targets for;
a novel therapeutic target for;
an important target for gene therapy;
is considered an effective approach to improving
新的机制包括、潜在的机制：a novel mechanism involving;
give insight into the regulatory mechanisms;
provide insights into possible cosmetic and therapeutic applications.
然而、转折：while; nevertheless; However;Whereas; but
总而言之：Taken together; In summary; All in all;In a word; In sum; Taken into account
导致、结果：resulting in；leadingto；as a result of; Resultform; As; So; Because; So as to; Sothat
因果承接: Hence; Therefore; For this reason; Thus;So; Thereby
另外：Moreover；Furthermore；Besides； Inaddition； additionally； at the outset； it is obvious to; above all；Moreover；Naturally；Even within
Prep:In spite of ；In despite of
也...,同时... ：a combination of both；Also；Meanwhile；While
换句话说,另一方面：in otherword；On the other hand
在...方面：in terms of；in this respect；in this regard
导致：result in + n
因为：due to + n
例如：such as the + n, n, or n
exact mechanisms…are not yet known;
The mechanism by which ... Yet to be shown;
have not yet been elucidated;
the role of genes in male pattern baldness have beendocumented in previous reports;
No convincing explanation has yet been proposed for thisdecline in hair follicle density;
The answer is not obvious, but biologists have suggestedseveral notions recognizingthat skin molting (and the shedding of its appendageal products) is inherent tothe integument of all organisms;
How the cycle spreads in waves is not clear, but experimentalstudies suggest that;
Where the rhythm center rests in the follicle is unknown;
However, what ... Is debated;
Concrete exidence for the theroy is scant, although ... Hasbeen reported... While... Does not;
.... Is not yet clear;
Although it is comparatively simple to ... the molecularsign posts are less clear;
Although their function is not yetclear, a group of molecular markers of the anagen follicle bulb/matrix has beendescribed;
The basis for the latter newly programmed structural changesis not yet clear, although its elucidation will be of great practical value 机制不明，但意义重大
知道现象，不知道具体机制：Although we now know their expression pattern, we knowvery little about how any of these adhesion molecules act in anageninitiation, development, or hair cycle control;
Although the answers we have are stillunsatisfactory;
What in thesebaceous gland/sebum is responsible for sheath dissociation is undercurrent study;
The role of these cells in catagen development is not clear not clear.
the rationale for choosing these mice is that;
For this reason;
It is suggested that hair follicle cycling may have arisen; because it offers a mechanism whereby animals could 1）；2）；3）；4）;
but experimental studies suggest that;
Theories proposing a mechanism for this hair follicle
In understanding anagen we will have to acquire greaterinsight into the controlsof tissue regeneration, the signals initiating anagen growth and stemcell arousal, the character of the molecular system controlling follicle/shaftcharacter, the mechanism of shaft outward movement, and shaft sheathdissociation
猜想： hypothesis for；
We assume that at least some aspects of the pathwaw activatedare common to the two situation;
it is tempting to speculate that;
it is reasonable to assume that;
has been documented;
have been documented in previous reports;
Studies have also shown the imperativerole of;
Recent works suggest that;
Transgenic mouse studies have demonstratedthat;
Early workers demonstrated;
similar results have been found by;
experimental studies suggest that;
It has been found that;
It has been observed that;
This observation suggests that;
It was suggested that;
It is also notable that;
It has long been known that;
Such studies indicate that;
Biochemical studies also support the notion that;
Evidence suggesting that;
The presence of this molecule suggests that it plays a role in the integrity ofthe papilla over the cycle;
It is generally hold that;
Gene expression and immunolocalization studies of ... Showthat;
Direct evidence for this conclusion is found experimentallywhere;
The notion that... was tested by invitro studies;
This finding supports the idea that;
Mouse experiments have shown that;
Recent work has found that;
Direct studies show that..
毛囊周围炎性细胞浸润：In early catagen in the rat (but notthe mouse, Ref. 428), there is also a light mononuclear inflammatory cellinfiltrate surrounding the lower follicle
限制…的行为：restrict the action of…by preventing
leading to the destabilization of MITFmRNA；
Pulsed dye laser treatment of vascular lesions generally results inpurpura
…result in, … that occurs due to a …
Pulsed dye laser treatment of vascular lesions generally results inpurpura, an immediate bruise-like discoloration that occurs due to ashock wave effect
These disordersare poorly controlled and cannot currently be effectively treated, mainlydue to our lack of understanding of hair follicle function.
It is believedthat androgens exert their effects on hair follicles via the mesenchyme-deriveddermal papilla cells by altering the regulatory paracrine factors produced bythe dermal papilla itself and affect the other follicular components.
研究目的，提出问题：In this section we focus on thecell lineages making up the cycling portion of the follicle. We would liketo know from where each of the follicular layers arises and what controlstheir differentiation. Although the answers we have are still unsatisfactory,some basic principles are clear
调控、调节：Hair cycle-dependent changes in the follicular micro-anat- omy aregoverned primarily by the WNT, TGF-b/BMP, hedgehog, EDAR, FGF and IGFsignalling pathways ；
It has recently been demonstrated that several long non-coding RNAs,such as TINCR and ANKR, are involved in the control of epidermaldifferentiation and stratification；
It has been estimated that between 30% and 80% of the protein-coding genesmay be regulated by miRNAs ；
Thus, miRNAs are involved in theregulation of diverse biological functions during development, differentiationand pathological conditions
... 影响... 产生... 效应 EGF and TGF-a which impact follicle growth alsostimulate follicles to release various MMPs and lyse collagen gels
相同条件下，存在某种物质和不存在某种物质，所产生的影响不同：Whenwhole follicles (sheep, horse,human) are cultured in the presence of their own sebaceousgland/mid-follicle region, the shaft grows out free of sheath. When the samepreparation is grown in the absence of the sebaceous gland/mid-follicleregion, the shaft grows out with the sheath
MITF is paramount for melanocyte developmentand melanoma pathogenesis.
在..上做出许多努力：In thepast 25 years, great efforts have been made to create substitutes thatmimic human skin
在...领域：Indeed, inthe field of skin tissue engineering, despite the variety of approachesproposed, none allows the formation of hair follicles in in vitro cultures
Support for the unique and conserved character of a givenfollicle is most powerfully demonstrated by transplantation
Follicles placed in vitro have been shown to havethe ability to lyse collagen gels and to synthesize and secrete variousMMPs including interstitial collagenase, stromelysin-1, gelatinases,collagenase, and matrilysin (MMP-7)
相同现象，可能相同机制：The similarity of the early anagen finger invading intothe dermis to invasive basal or squamous carcinomas suggests a commonmechanism between the down-growing follicle and invasive skin tumors
知道现象，不知道具体机制：Although we now know their expression pattern, we knowvery little about how any of these adhesion molecules act in anageninitiation, development, or hair cycle control
机制不明：Theseparadoxical effects of androgens on human hair growth have long been a mystery.
通过...方式，或...方式或兼而有之，结合原因解释：It was suggested that the IRS breaks up at this levelbecause of enzymes secreted by the ORS, by components of thesebaceous gland, or a combination of both
两种功能并列表达：Paradoxically, this patterning gene plays a structuralfunction in the mature follicle in addition to its patterning rolein early development
两者前后比较：It is notable that in clinical hair disorders such as malepattern baldness and alopecia areata (ophiasis type) the respective regions aredramatically circumscribed and differ substantially in their clinical courseand prognosis (94); in the former, the bald area corresponds to theneural crest mesoderm, whereas in the latter, the bald area correspondsto the somiticderived mesoderm.
在…方面有提高，进步：these patients also demonstratedsignificant improvement in facial wrinkles
相反：With nonsurgical laser treatments painis mild; usually no anesthesia is required. In contrast, surgical lasertreatments are nonspecific and affect all skin components equally.
举例： such as后只加一个the：those with larger vessels may also requiretreatment with a continuous-wave laser, such as the krypton, argon,or normal mode Nd:YAG lasers
列举作用因素，重要作用：The regulatory gene families mentioned above,which impact hair morphogenesis, such as FGF, Wnt, TGF-b, andhedgehog, undoubtedly play a critical role in the patterning of numerousdevelopmental systems .
As mentioned above, the cycling portion of the anagen follicle is asolid epithelial cylinder made of embedded,concentric, unique cylindrical layers
段落列举，句式列举说明：One of the major chromophores ismelanin；
Another major skin chromophore is hemoglobin in the red blood cells；
Other common chromophores in the skinare the ink particles in a tattoo.
the erbium:YAG laser offers several advantages for laserresurfacing. These include less pain, faster healing (30–50% faster thanwith CO2 laserresurfacing) and less redness of the skin after healing. The majordisadvantage of the erbium:YAG laser is that, unlike the CO2 laser, itdoes not seal blood vessels in the dermis.
列举、总结生长期的各个方面：In understanding anagen we will haveto acquire greater insight into the controls of tissue regeneration,the signals initiating anagen growth and stem cell arousal, the characterof the molecular system controlling follicle/shaft character, themechanism of shaft outward movement, and shaft sheath dissociation
分析、列举原因：Is this due to the fact that a limited number of mitoses of the transit amplifying cell population becomes exhausted (84)? Or, is it dueto a change in the paracrine factor milieu, such as to theaccumulation of growth inhibition and proapoptotic agents, or to changesin activities of perifollicular mast cells and macrophages, or to a combinationof all of the above
列举因子上调下调表达：Other molecules that could serve asanagen-supporting signals include insulin-like growth factor I receptor(IGF-IR), KGF, and HGF (297), which are downregulated, and BDNF,NT-4,NT-3, and TGF-b1,which are upregulated upon catagen initiation.
需要超过／至少两周的时间消失：require up to two weeks to completely disappear
持续时间：persist as long as；
may persist as long as two weeks after treatment
常用的两种方式：There are two types of resurfacinglasers in common use: erbium: YAG and CO2.
whetheror 句型：Whether that signal is primary to epidermis or secondary toan inductive stimulus from the dermis is debated
相同点与不同点同时表达：Although these two processes sharemany features, they differ from one another in at least one fundamental way: in the one a whole structuregenerates from a primitive epidermis (morphogenesis), and in the other,a partial structure generates from adult tissues
An inverse correlation between MITF and miR-218 expression was found inhuman primary skin melanocytes and melanoma cell lines
描述变化，区别的三种方法，结构从下往上，部位从高往低，结构由远及近：The thickness and cellularity of theORS vary with the level of the follicle: it is single-layered just aboutthe bulb, higher up it is composed of multilayered cuboidal cellswhich accumulate glycogen, and at the level of, and distal to,the sebaceous gland it becomes multilayered and is structurally similar tothe epidermis
It is ... That 句型： it is important to recognize anddistinguish the fect that ...
随着生长期进展... With the development of anagen....
迫切的需求：A cosmeticapplication of a laser is very demanding
大得多：It is much larger than its runner-up,the liver.
最重要的功能：Its most obvious and perhaps mostimportant function is to provide a protective covering for the restof the body and an interface with the environment.
功能丧失：If this function is compromised
Not only+句子 but also+句子不仅有…功能，还具有…功能：they not only haveessential roles in normal physiology and development but also have validatedroles in the promotion or suppression of neoplasia
Not only... Butalso+名词的用法：Thus the growth phase of the shaft,anagen VI, not only serves as the mainproduction period for the fiber but also as a system for transportingskin secretions, debris, and parasites/microorganisms from the pilary canal tothe skin surface
Not only... But also+句型的用法：in fact, not only do the types of keratins expressed varyover the cycle the cycle, but the character of the shaft itself alsovaries.
Recent developments in pharmacological approaches to manipulate miRNAlevels in vivo, including tissue-specific delivery, hold great promise fornovel therapeutic approaches to treat cancer, including metastaticmelanoma;
Therefore, the identification of MITF-targeted melanogenic miRNAs shouldgive insight into the regulatory mechanisms of melanogenesis and provide newpromising targets for depigmentation.
引用别人文章基础，提出假设：Because homeobox gene transcriptionfactors play a pivotal role in body and limb development and are expressed in the follicle, it isreasonable to assume that they also impact hair character.
影响因素多，环境复杂，并可作为... 的原因：Because many patterning genes are expressed in thefollicle, the situation is complex. It may be that the variableexpression of patterning genes gives each follicle a unique address and thus aunique morphology
通过下游基因发挥作用：they act by orchestracting theexpression of many downstream genes.
... 必不可少，缺乏导致：It wasfound that Hoxc13 is essential tonormal hair shaft development. In the absence of functional Hoxc13, hair shafts form but are friable
下定义：... 结构把... 从... 分开；同位语：The outermost cylinder, the ORS, separates the whole hair shaftfactory from the dermis and subcutis.
概念，能力，特性，实验研究表明：either and/or ：The notion that either the sebaceous gland and/or the pilarycanal walls in this region have the property to dissolve the sheath wastested by in vitro studies.
主语从句，宾语从句，同位语：That the ORS produces catagenproducing growth factors, likeFGF5 and neurotrophins, supports the idea that the ORS plays animportant role in regulating the cycle
生长期的定义：Anagen, then, is the period in thecycle when the lower follicle regenerates itself, reconstructs its hair shaftfactory, and actively generates a pigmented hair shaft
毛干的定义：The hair shaft is essentially aproduct of proliferating and terminally differentiating keratinocytes thatdiffer substantially from epidermal keratinocytes in their biochemical andkeratin gene expression
退行期定义：This phase, catagen, is a highlycontrolled process of coordinated cell differentiation and apoptosis, involvingthe cessation of cell growth and pigmentation, release of the papilla from thebulb, loss of the layered differentiation of the lower follicle, substantialextracellular matrix remodeling, and vectorial shrinkage (distally) of theinferior follicle by the process of apoptosis.
退行期八个亚期dividinto：The catagen stage of the hair cyclehas been divided into eight subphases beginning with late anagen and ending in early telogen(357, 542).
概念是... 特点是... ：The Notch signaling system is one of the major pathways involved in cell fatespecification and is characterized by the interaction between two types oftransmembrane proteins: the Notch receptors and the Delta/Jagged families ofligands
Hair follicledevelopment and its postnatal regeneration are characterized by dramaticchanges in its microanatomy and cellular activity, which are controlled bymultiple signalling pathways, transcription factors and epigenetic regulators, includingmicroRNAs (miRNAs)
Mir定义：miRNAs are small single- stranded RNA molecules, which are only about 22nucleotides in length. They control gene expression at the post-transcriptionallevel by changing mRNA stability, promoting mRNA degradation and negativelyimpacting translation
句子衔接：at the ouset it is obvious to; aboveall. Moreover;
Our focus in this review is on the matureand its contorls. Weattempt here to integrate ...whichwar pretty well known,except for, we do not ...because . Ourgoal is to;
we present in this section a broad overview of the biology of hair follicle growth andcycling because it is relevant to everything that comes hereafter;
It is important to appreciate that there is an;
Although we do not know the... we do know;
it is believed;
时间衔接：The catagen stage of the hair cycle has been divided intoeight subphases beginning with late anagen and ending in earlytelogen
实验现象或结果描述：Transcriptional activation, theearliest observed changes of anagen, occurs in the cells of the papilla and thesecondary hair germ
之前：Whole skin explants have been used to study hair growth.Early attempts to grow embryonic skin in vitro demonstrated that
现在：More recently, mature whole skin from mice and humans has beenused to study the hair cycle
目前的方法：It has been demonstrated that dissected mature human anagenfollicles can be successfully grown in culture
转折，不足之处：Although these follicles continue to grow for ;9 days inculture and are thus useful for studying the anagen phase and the onset ofcatagen, they do not traverse the full hair cycle and do not generate newfollicles
有些成功，有些不成功：Although growing dissociated cells,both mesenchymal and epithelial from mature hair follicles has beensuccessfully achieved, generating follicles in vitro from these cells has beenless successful
A major current challenge for the laboratory assessment ofhair follicle growth is to;
No such system is now available;
In fact, we currently have no good in vitro system forassessing the vellus to terminal switch, for measuring anagen (growth phase)induction, or exogen (shedding) induction.;
For this reason
Before we explore the importance of miRNAs for HF biology, we would like tofurther address additional and very basic questions relating to miRNAfunction.
This will enable us to highlight current limitations in our understandingof miRNA biology and how studying the role of individual miRNAs in the context of skinbiology may fundamentally contribute to progress in answering some of thesequestions:
What is the reasonfor such a largenumber of post-transcriptional regulators
It has beenspeculated that there is a relationship between miRNA number and organismalcomplexity.
Indeed, miRNA profiling studiesin the HF during morphogenesis and cycling revealed the spatio- temporalexpression of a large number of miRNAs (24–26), which indicates the significanceof miRNAs in gene expression regulatory circuits of a complex mini-organ suchas the hair follicle.
And indeed, as we will highlight inthe following sections, miRNAs are essential for HF development andhair growth.
Despite many years ofintensive research into target genes of miRNAs, this issue is notresolved. Initial and serious attempts to address this question indicatethat miRNAs can regulate on average at least 7 (27) to up to 100genes
over 5000 human genes are likely miRNAtargets and, indeed, target sites may not be restricted tothe 3’UTR
Experiments withmiRNA knock-out or their overexpression indicate that the impact of the loss ofa miRNA can be broad.
For example, complexchanges in the HF and skin morphology induced by miR-125b overexpressionwere associated with the repression of over 800 transcripts, whichwere predicted to be conserved miR-125b targets
However, there is also somejustification to focus on a very few key target genes (30).
Recent years havebrought tremendous progress in regard to target gene assays, whichsignificantly help us to improve our knowledge of the nature of targetgenes and their number.
intensive studies in Drosophila by Brenneke et al. (28) showed thattargeting does not need to involve a classical seed sequence.
intensive studies in Drosophila by Brenneke et al. (28) showed that targeting doesnot need to involve a classical seed sequence.
This may explain why a miRNA is normally around 20 nucleotides long and not justaround 8 nucleotides.
Therefore, the inconvenient answer is that there may be a much more complextargeting pattern when we generally take into consideration and that thereare many more ‘non-canonical’ targets that we should study
Therefore, this issue is still controversial despite recent comments in Nam et al. (34)that ‘. . . noncanonical site types are either not effective or less effectivethan 6-mer sites’, with 6-mer sites by far the least effective canonical sites,and the clarification of the structural importance of the seed sequence formiRNA function and target recognition
Although initial studies indicated that miRNAs preferentially targetthe 3’UTRof mRNAs
However, the overall relevance of these non-canonical target sitesespecially for ancient and highly conserved miRNAs awaits further studiesand clarification.
The rule of thumb here is to talk in percentages rather than foldchanges.
The majority of experimentsindicate that one can expect a change in expression of the averagetarget gene on the mRNA and protein level of 20–50%.
Taken into account that these numbers only reflect the loss offunction, one can assume – including dramatically increasedexpression of the miRNA – a rough total range starting at 40%.
Does it matter if a miRNA varies twofold for a buffering function?
Is a 50-fold change of a lowly expressed miRNA more important thana 1.5-fold change of the top expressed miRNA?
In short, all these can be summed up with a conservative rule froma more dogmatic point of view: miRNAs preferentially bind to the 30UTR region ofa mRNA, with the most effective and functional sites recognized be the8-mer seed. This will result in a change in expression of the set of targetgenes of about 15–40% on the mRNA and the protein level.
This can also be used by the cell to suppress unwanted transcripts.
Therefore, to identify disease- or process-related miRNAs, it seems wise toselect the ones that are massively altered between two states andhave a substantial expression level in one of the states.
Indispensable roles for miRNAs in the development and organogenesis havebeen demonstrated by cell-specific or tissue-specific interferences with miRNAbiogenesis
In the skin, constitutive surface ectoderm-specific deletion ofmiRNA processors Dicer or Dgcr8 during embryonic development (E14.5–E17.5) resultsin the severe abnormalities in HF development characterized by theinability of the hair follicles to invaginate into the dermis, which leadsto major structural defects and failure to produce a hair shaft
Consistently, the ablation of the vital components of RISC components Ago1 andAgo2 also leads to marked changes in skin morphogenesis, includingthe formation of HF cysts
Naturally, miRNAs are essential not only for HF development, but also forits postnatal growth.
When Drosha or Dicer is deleted after HF initiation has been completedfully developed hair follicles (P12-P14) exhibited abundantapoptosis in the hair matrix and structural changes in the hair shaft, whicheventually led to HF degradation
In summary, these studies have provided striking evidence on howglobal loss of miRNAs in the embryonic epithelium dramatically changesthe molecular interactions between epithelial and the dermal cells resultingin the failure to form a normal hair follicle, and on how miRNAs arerequired in adult hair follicles for proliferation and apoptosis control.
These differences in miRNA expression profiles in the differentepithelial lineages of the skin are believed to contribute to theestablishment of these very same lineages.
Even within the hair follicle, major differences in miRNA expression areevident between the bulge, outer root sheath (ORS) and hair matrix cells,while surprisingly high similarities were observed between the miRNAprofile of the bulge and basal epidermal cells
To follow our view that highly expressed miRNAs are generally theimportant miRNAs in a given cell type, we would like to start ourexploration of individual miRNAs with miR-205.
miR-205 and miR-203 can be regarded as the squamous epithelialmiRNAs
This study confirmed miR-205 as an important regulator of the PI(3)-kinasesignalling (50) and as a HF stem cell activator that is crucially importantfor HF morphogenesis
It has been shown that miR-125b acts as a repressor of HF stem cell differentiation, andtherefore indispensable for anagen onset
Indeed, aberrant expression of miR-125b in the outer rootsheath leads to an expansion of stem- like cells with theirimpaired capacity to differentiate, which eventually leads to the developmentof alopecia
Yi and colleagues have demonstrated that miR-205 is highlyenriched in the epithelial progenitors and stem cells during skindevelopment.
They have also shown that it is vitally important for HFdevelopment
The deletion of miR-205 results in severe developmental defects and aperinatally lethal phenotype, which is very rarely seen in miRNAknockout mice.
miR-205 promotes stem cell expansion during early HFdevelopment and its ablation negatively impacts proliferation ofstem cells and their direct progeny, while not exhibiting an effect on highlyproliferative hair matrix cells.
Interestingly, vitamin D receptor (VDR) serves as one of the criticaltarget genes of miR-125b in follicular cells, and decreased VDRlevels explain several of the defects in HF differentiation in miR-125btransgenic mice
This role of miR-125b is consistent with its functions in regulating theactivity of different stem cell types outside of the skin, including embryonicstem cells (51), hematopoietic stem cells (52) and neural stem/progenitor cells
Constitutive overexpression of miR-24 in proliferating cells duringskin morphogenesis leads to abnormal HF development associatedwith reduced proliferation and premature differentiation.
It was discovered that Tcf3 acts as one of the targets of miR-24
Tcf3 is the transcription factor expressing in thefollicular stem cells and their progenies in the outer root sheath tomaintain their undifferenti- ated state
Therefore, the lack of miR-24 expression in proliferating cells contributesto the maintenance of their proliferative activity
E2F2 was identified as one ofthe critical miR-24 targets
MITF knockdown in primary melanocytes resulted in upregulation and downregulationof several miRNAs, suggesting their potential involvement in skin andhair pigmentation
How miR-211 is involved in HF pigmentation remains unclear
Several miRNAs have been identified which can regulatemelanogenesis by targeting MITF, including miR-340, mir-137,miR-182, miR-25 and miR-218
Apoptosis plays an essential role for proper HF cycling and the maintenanceof homoeostasis
Different cell populations in the HF exhibit different susceptibilityto apoptosis: highly prolif- erative matrix keratinocytes andpigment-producing melanocytes are sensitive to pro-apoptotic or stress stimuliand dermal papilla fibroblasts are more resistant to apoptosis
Studies with targeted Dicer and Drosha deletion clearly demonstrated theimportance of miRNAs for the protection of HF cells against apoptosis,because mutant hair follicles undergo massive apoptosis
that miR-205 may play a protective role against apoptosis in thehair follicle.
Catagen induction and apoptosis are significantly reduced in theskin of p53 knockout mice
p53 triggers apoptosis by transcriptional activation ofvarious proapoptotic genes, including Bax, Noxa and Puma, or byrepression of anti-apoptotic genes, such as survivin.
However, how p53 itself is regulated by miRNAs remains largely unknown
The exploration of a miRNA/p53 feedback circuitry associated with the HFgrowth cycle could bring a new understanding of the molecularmechanisms controlling catagen.
The area of miRNA-mediated gene expression regulation in the HFmesenchyme (dermal papilla and perifollicular connective tissue sheath) remainslargely underinvestigated.
All discoveries about the impact of miRNAs on HF development and cyclingwere made based on the in vivo deletion of miRNA-pro- cessing enzymes inkeratinocytes, while the consequences of miRNA loss in the follicularmesenchyme have not been explored yet.
Therefore, many intriguing questions await answers.
The only study that has started to address the function of miRNAs inmesenchymal components of the HF has compared miRNA expression between baldingand non-balding dermal papillae.
However, the functional significance of these findings remains elusive
And although differences in expression may be important, we cannotemphasize enough the importance of absolute expression levels, which was notclarified by Goodarzi et al.
This will provide new and important insights into fundamental mechanismsthat regulate cellular activity and cell fate decisions inside and outside ofthe skin. Eventually, these findings will be highly important for thedevelopment of novel miRNA-based drugs and therapies.
发挥作用：This indicates that the dermal papilla plays a main rolein androgen- mediated effects in the hair follicles；
It is believedthat cell signals may play a key role in regulation of cell growth, celldifferentiation and epithelial appendage formation ；
Insulin-likegrowth factor-I (IGF-I) is a highly potent mitogen
miRNAs and theirtargets form remarkably diverse regulatory networks, playing akey role in the execution of gene expression programmes in thedifferent cell lineages of the hair follicle.
This review summarizes the roles of miRNAs in the control ofhair follicle development, cycling and hair pigmentation, emphasizes theremaining problems/ unanswered questions, and provides future directions inthis rapidly growing and exciting area of research.