Development of the Upper Lip

ORIGINAL ARTICLE Development of the Upper Lip

Craig W. Senders, MD; Erik C. Peterson; Andrew G. Hendrickx, PhD; Mark A. Cukierski, PhD

Objectives: To affirm and reanalyze George L. Streeter’s sal, medial nasal, and maxillary prominences form the “merging theory” of upper-lip development in primates by nose. There is fusion of the maxillary prominence with observing progressive embryologic stages in facial devel- the medial nasal prominence. This fusion has not been opment using scanning electron microscopy (SEM) and to previously described. This has resulted in a modifica- further understand upper-lip development. tion of the current theory of upper-lip development into one we refer to as the “dynamic fusion theory.” Design: The study was conducted at the California Re- gional Primate Research Center, Davis. Twenty primate em- Conclusions: The dynamic fusion theory explains the bryos (Macaca fascicularis) and 2 fetuses were examined merging process of the mesenchymal and ecotodermal with SEM. The development of the frontonasal promi- layers of the facial prominences that contribute to the up- nence, maxillary prominence, medial nasal prominence, and per-lip formation. The dynamic fusion theory of facial lateral nasal prominence were sequentially observed. The prominence movement details the interaction between contribution of these prominences to the formation of the epithelial layers: both epithelial layers must fuse prop- upper lip and nose were carefully analyzed. erly to avoid cleft-lip deformities.

Results: The maxillary prominence and medial nasal prominence form the upper lip, whereas the lateral na- Arch Facial Plast Surg. 2003;5:16-25

UR QUEST for knowledge created 3-dimensional reconstructions by and understanding has a best-fit method. His 3-dimensional re- led to an exploration of constructions of the face are remarkable, the embryologic develop- especially when one considers that his ment of the upper lip. The work was done without the assistance of lateO Franklin P. Mall ignited the flame by computer-aided digital analysis. founding the department of embryology at Our work used scanning electron mi- the Carnegie Institution of Washington, croscopy (SEM), which has the advantage Washington, DC, which today contains one of allowing a full analysis of facial develop- of the most well-respected human em- ment at greater resolution of surface struc- bryo collections. He bequeathed the col- tures. A primate model was used because lection to the late George L. Streeter, MD, of the lack of human embryonic tissue. All who devoted his life to studying the devel- embryos were used in multiple research opment of the embryo.1 It is the great work projects. Although Streeter’s work is re- of Streeter, who discovered and devel- markable, SEM analyses were used to con- oped many of the insights into embryo- firm and alter certain aspects of his work. logic staging and development, that stands as the foundation for many of today’s in- METHODS quiries. Facial development has always been difficult to study because of the translu- Adult female cynomolgus monkeys (Macaca fas- cency of the embryo and limited visualiza- cicularis) were housed individually in alumi- tion caused by the head-flexed position of num cages at the California Regional Primate Re- search Center, Davis, and maintained in embryos. accordance with standards established by the From the University of Streeter explored new techniques to Federal Animal Welfare Act and the Institute for 1 California, Davis. Dr Cukierski overcome obstacles. He studied embry- Laboratory Animal Resources. Animal rooms is now with Merck Research onic histologic sections and used these were maintained on a 12-hour light-dark cycle Laboratories, West Point, Pa. sections as a framework. Streeter hand- (lighted from 7 AM to 7 PM) with a year-round

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 temperature of approximately 22°C and 60% relative humidity. Monkeys were fed twice daily with Purina Monkey Chow (15% Table 1. Catalog of the Embryos Analyzed protein) (Ralston Purina Company, St Louis, Mo), and water was According to Stage Distribution, Estimated Age, provided ad libitum by automatic Lixit devices (Lixit Animal Care and Crown-to-Rump Lengths Products, Napa, Calif). Menstruation was detected by visual ex- amination of the external genitalia or by detection of blood on a Stage Estimated Age, d Crown-to-Rump Length, mm cotton tip swab after insertion into the vaginal canal. Females were 12 28 6 mated by natural insemination by housing with a single fertile 13 26 7 male for approximately 2 hours every other day over a 5-day pe- 14 29 7 riod at midcycle. The middle of the mating period was desig- 16 31 10 nated as day 0 of pregnancy. Pregnancy was confirmed by posi- 16 35 9 tive radioreceptor assay tests for chorionic gonadotropin in serum.2 16 32 10 16 31 10 Embryos were removed by hysterotomy, placed in phosphate- 16 32 11 buffered saline, and dissected free of the placenta and develop- 17 37 12 mental adnexa. The embryos were fixed by immersion in 2% glu- 17 33 13 taraldehyde, 2% paraformaldehyde in 0.1M cacodylate, or 17 32 12 phosphate buffer at pH 7.3 and then measured and photo- 17 36 12 graphed intact. The Carnegie system for staging human em- 18 38 16 1 18 35 16 bryos was used to stage the embryos externally, and subsequent 21 40 20 histologic analysis of several internal organs was used for con- 20 39 20 firming of stage.3 The fixed heads were removed using a razor 20 39 21 blade and stored in refrigerated buffer until processing. Other in- 21 41 19 vestigators used other tissues. The tissues were dehydrated in 21 42 19 graded series of ethanol and critical-point dried using liquid car- 23 46 26 Fetus 52 33 bon dioxide as a transition fluid. The dried specimens were Fetus 52 Unmeasurable mounted on stubs with double-stick tape or conducting silver paint and coated with palladium gold in a Denton Vacuum evaporator (Moorestown, NJ) or sputter-coated with gold in a Polaron E51 coater (Ladd/Polaron, Williston, Vt). The specimens were exam- tral surface of the stomodeum, which is still dispropor- ined in an ETEC Autoscan U-1 (Applied Materials, Santa Clara, tionate to the size of the corpus but has become smaller Calif) or an ISA SS60 (ISA Inc, Louisville, Ky) scanning electron with the merging of the mandibular prominences. microscope. After photographing the heads intact, we made further dissections (using microdissecting knives) on the dried speci- EARLY STAGE 16 mens. The heads were then recoated and examined as above. A total of 22 specimens ranging from stage 12 to fetus were exam- A major advance in stage 16 (Figure 3) is the appear- ined (staged according to Hendrickx,4 O’Rahilly,5 and Wilson 6 ance of the nasal pits, which appear to end blindly and are et al )(Table 1). located more medially than their precursors, the nasal placodes. The nasal pits begin as rounded spheres and de- RESULTS velop into “comma” shapes, pointing slightly laterally by late stage 16. The maxillary prominence is well devel- STAGE 12 oped, much like the lateral and medial nasal prominences. As the maxillary prominence develops toward the Figure 1 shows the 3 prominences of stage 12, the fron- median plane, the caudal portion of the frontonasal groove tonasal, maxillary, and mandibular (see Table 2). The starts to move cranially. The lateral and medial nasal promi- frontonasal prominence forms the forehead and the ros- nences are well developed and easily distinquished cau- tral boundary of the stomodeum (primitive mouth). The dally, but the separation is ill-defined cranially. The me- mandibular prominence forms the caudal boundary of the dial nasal and maxillary prominences merging caudally primitive mouth. The maxillary prominence is ventral to form the paired labial furrows, which are located lateral the developing eye. The mandibular arch has a median to the frontonasal groove along the upper lip. The man- groove (mandibular groove), which separates the devel- dibular groove remains prominent. Lingual swellings are oping branchial arches. The nasal placodes are barely dis- very evident just lateral to the mandibular groove. The me- cernible. The mandible is separated by the stomodeum, dian mandibular groove continues to become shallower. which is disproportionate to the size of the corpus. The nasolacrimal groove is very distinct. The lateral and medial nasal prominences and the maxillary prominence STAGES 13 AND 14 are merging at the nasal sill. The lateral and medial nasal prominences form the nasal sill, whereas the maxillary The nasal placodes have become more pronounced in prominence supports the nasal sill caudally. The stomo- stages 13 and 14 (Figure 2) and have moved slightly deum is still elongated across the corpus but is achieving medially from their stage-12 positions. The maxillary na- a more distinct shape with medial movement of the max- sal prominence and lateral nasal prominence have be- illary prominences. come visible and are positioned more medially. The maxillary prominence is more distinct. The nasolacrimal LATE STAGE 16 groove is visible separating the maxillary and the lateral nasal prominences. The mandibular groove has become Small bridges of epithelial tissue span the nasal sill re- shallower. The frontonasal groove is located on the ven- gion between the lateral and medial nasal maxillary promi-

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Figure 1. Scanning electron microscopic views of stage 12 Macaca fascicularis embryo. A, Frontal view in which the frontonasal process, stomodeum, and developing pharyngeal (branchial) arches are evident. The mandibular prominence develops from the first pharyngeal arch (long, thin arrow). Two other pharyngeal arches are located caudal to the first arch. A large frontonasal groove can be seen medially on the embryo (short, thick arrow). B, Oblique view with some corpus damage evident. The pharyngeal arches are evident as is the wide stomodeum.

Table 2. Index of Terms

Stages Terms Term Definition Are Observed in Found in Figures Lateral nasal prominence The lateral boundary of the nasal placode, forms the ala and lateral 14-18 2A-B, 3A-D, 4A, 5A-B, 6A-C nose Medial nasal prominence The medial boundary of the nasal placode, forms the dorsal ridge of 14-18 2A-B, 3A-D, 4A-B, 5A-B, 6A-C the nose and columella Maxillary prominence Forms the rostral boundary of the stomodeum, portions of the upper 14-18 2B, 3B-D, 4A-B, 5A-B, 6A-C lip, and upper cheek region Mandibular prominence The caudal boundary of the stomodeum, forms the lower lip, chin, 12-17 1A-B, 2A-B, 3A-C, 4A, 5A-B and lower cheeks Frontonasal prominence Surrounds the ventral part of the forebrain, and forms the forehead 12-16 1A-B, 2A-B, 3B and rostral boundary of the stomodeum prior to maxillary prominence movement Frontonasal groove A groove located medially between the merging medial nasal 12-17 1A-B, 2A-B, 3A-B, 3D, 5A-B prominences Labial furrow Paired furrows formed by the merging maxillary and medial nasal 16-17 3A-D, 4A-B, 5A-B prominences Mandibular groove A medial groove formed by the merging mandibular prominences 12-17 1A, 2A-B, 3A-B, 5A-B Maxillary medial groove A medial groove caudal to the fused medial nasal prominences 17-21 5A-B, 6A-D, 7A-B, 8A-B Hypophysial pouch, Projects from the roof of the stomodeum and lies adjacent to the 16 3D “Rathke pouch” floor of the diencephalon; these cells will form the anterior pituitary gland Stomodeum The primitive mouth 12-23 1-9 Nasolacrimal groove A groove that separates the lateral nasal prominence from the 16-18 3A-D, 4A-B, 5A-B, 6A-B maxillary prominence Nasolacrimal duct Forms within the thickening of the nasolacrimal groove Not seen in photographs . . . Mandibular labial swelling Epithelial swellings that decrease during development and form parts 16-17 3A-C, 5A-B of the lower lip Epithelial bridging Epithelial cells that span merging prominences 16 4A-B Primordial choana An opening between the nasal and oral cavities that lies posterior to 18 6D the primary palate; this is distinct from the definitive choana that separates the nose from the nasopharynx after the secondary palate is formed

nence by late stage 16 (Figure 4). Epithelial bridging groove has been decreasing due to the medial move- is even more evident than before between the maxillary ment of the medial nasal prominences. The stomodeum prominence and the medial nasal prominence. Looking is becoming more proportional to the size of the corpus. rostrally at the underside of the palate, one can see the forming of the paired labial furrows and frontonasal STAGE 17 groove. In some cases, the epithelial bridging is seen in the labial furrows. The persistent labial furrows have been A greater degree of development of the nasal pits is appar- pushing caudally since early stage 16 as the frontonasal ent in stage 17 (Figure 5). The paired labial furrows are

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Figure 2. Scanning electron microscopic views of stage 14 Macaca fascicularis embryo. A, This frontal view of an approximately 29-day-old embryo (stage 14) shows that the nasal placodes have moved medially from their stage-12 positions. The nasal placodes consist of the medial (thinnest arrow) and lateral (medium-thickness arrow) nasal prominences. The mandibular groove is closing with the developing mandibular prominences (shortest, thickest arrow). The frontonasal prominence is located rostral to the frontonasal groove. B, This oblique view shows some corpus shrinkage. The nasal placodes are visible, and the mandibular prominences can be distinguished.

less prominent than they were in stage 16. The maxillary appearance. The central lip (prolabium) is made up of the median groove can be distinguished from the frontonasal fused medial nasal prominences. The lateral lip is formed groove after the medial nasal prominences have merged me- from the maxillary prominences. The apex of the maxil- dially. The merged medial nasal prominences separate the lary median groove has moved caudally, although a me- frontonasal groove from the maxillary medial groove, which dian groove persists. Epithelial bridging is not seen. The is located caudally. The nasal pits have moved medially and mandibular median groove has filled in, leaving a smooth have become smaller and more comma shaped. However, lower lip. The appearance of the gum line on the inside of the maxillary and medial nasal prominences remain sepa- the lower lip has become evident. The primary palate has rate from each other. The frontonasal and medial nasal taken form ahead of the nasal septum. The stomodeum has prominences are in the process of merging together and a gullwinglike appearance owing to the disappearance of in some instances have almost completely limited the ap- the mandibular labial swellings and the almost complete pearance of the frontonasal groove. The maxillary and lat- merging of the medial nasal, lateral nasal, and maxillary eral nasal prominences have remained in a relatively con- prominences. The stomodeum has become narrower and sistent position relative to earlier stages. There is less more proportional to a human mouth. distinction between the medial and lateral nasal prominences as well as the maxillary prominences. The fusion STAGE 20 of these prominences at the nasal sill appears complete. The labial furrows have moved inferiorly without any rem- The stomodeum has a gullwinglike appearance and is gradu- nant of epithelial bridging. Epithelial bridging of the max- ally narrowing by stage 20 (Figure 7). The premaxilla and illary medial groove is not seen. The paired labial grooves nasal complex have moved ventrally. The premaxilla has have achieved a less distinctive appearance. The mandibu- a ventral position relative to the mandible. The nasal com- lar arch still contains a median groove that separates the plex is in its medial location. The nostrils each have a com- labial swellings but is becoming less distinct. The stomo- malike appearance where the point of the comma points deum has a very curvaceous appearance with the well- laterally and caudally at about a 45° angle. The maxillary defined mandibular labial swellings and the merging na- median groove remains inconspicuous and less promi- sal prominences. nent. The paired labial furrows are barely discernible. The site of future midline fusion between the lateral palatine STAGE 18 shelves and the septum is evident. The developing upper lip and gum can now be distinguished. The most distinguishing aspect of stage 18 (Figure 6)is the humanlike appearance and lack of distinction be- STAGE 21 tween prominences. The lip continues to show the maxillary medial groove. The paired labial furrows are evident The nostrils have remained comma shaped with a simi- near the sill of the nose only. Laterally, the lip has a smooth lar angulation in stage 21 (Figure 8). The nose has in-

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C D

Figure 3. Scanning electron microscopic views of early stage 16 Macaca fascicularis embryo. A, All major prominences are visible: the lateral nasal, medial nasal, maxillary, frontonasal, and mandibular prominences. The labial swellings (arrow), lateral to the closing mandibular groove, are prominent on the mandible. The frontonasal groove is present between the 2 medial nasal prominences and caudal to the frontonasal prominence. B, The pronounced maxillary nasal prominence (arrow) is clearly evident in this oblique view. C, A frontal view focuses on the right nasal placode and the migrating nasal prominences. There is evidence of epithelial bridging (arrow). D, Here, the mandible has been removed from the head. The photograph shows a ventral view up into the Rathke pouch (arrow) and at the nasal placodes. The frontonasal groove is present between the closing medial nasal prominences.

creased in length. The developing premaxilla still con- completely fused. The stomodeum has lost much of its tains a maxillary median groove, which is decreasing in gullwinglike appearance and continues to narrow. With subsequent stages. With the decrease in the maxillary me- the change in appearance of the stomodeum, the max- dian groove, the gullwing appearance has become more illary median groove has also been smoothed out and looks flattened. The paired labial furrows have disappeared. This almost human in appearance. is the last stage in which the maxillary median groove is evident in the developing embryo. The palate has begun FETUS its zipperlike closing of the palatine shelves from anterior to posterior. The fetal stage shows the greatest humanlike appearance (no figure available). The nostrils have retained a comma STAGE 23 shape. The developing eyes have become more pronounced. The developed upper lip appears smooth with- Many distinctive aspects of the future fetus appear in stage out any paired labial furrows. There is no distinction be- 23 (Figure 9). The nostrils still appear in a comma shape tween the medial or lateral nasal prominences and the but with the curved end pointing ventrally. The nostrils maxillary prominence. The stomodeum has lost the gull- have stopped moving medially. The palatal shelves are wing appearance in its smooth and even development.

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Figure 4. Scanning electron microscopic views of late stage 16 Macaca fascicularis embryo showing major epithelial bridging. A, The nasal pit has not yet pushed through into the choana. The medial nasal prominence is bridging to the lateral and maxillary nasal prominences. B, A close-up of the epithelial bridging (arrow), which is a result of dynamic fusion of the major prominences.

A B

Figure 5. Frontal (A) and oblique (B) scanning electron microscopic views of stage 17 Macaca fascicularis embryo show the formed nasal pits and the formed maxillary median groove (arrows) located caudal to the 2 merged medial nasal prominences. The frontonasal groove is now located rostral to the merged medial nasal prominences and above the maxillary median groove. The maxillary, medial, and lateral nasal prominences and the mandibular prominence are all evident.

COMMENT Streeter believed that ectoderm was never absorbed (fusion) between 2 prominences. Rather, he believed that Facial prominence movement guides anatomic facial de- the mesoderm from growth centers within a prominence velopment. The medial nasal, lateral nasal, and maxillary merged with neighboring prominences. Initially, this cre- prominences all contribute to the formation of the nose and ated a furrow (groove) that was filled in by additional me- upper lip. George L. Streeter7 hypothesized his views regard- sodermal growth. Streeter described this process as the ing the developing mesenchyme of the upper lip. Today we “merging theory”: have a clearer view of embryologic development through the use of SEM that has allowed us to confirm and modify The furrows that lie between them [prominences] on the sur- Streeter’shypothesis.WehavereinvestigatedStreeter’sviews face are smoothed out as the proliferation and fusion of the of human lip development using a nonhuman primate. growth centers [mesoderm] fill in beneath. Under these cir-

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C D

Figure 6. Scanning electron microscopic views of stage 18 Macaca fascicularis embryo. A, Evident in this view are corpus shrinkage, the merging eyes, and the gull-wing-like appearance of the stomodeum. The comma shape of the nasal pits due to the rotation of the nasal prominences is also evident. B, In this oblique view, there is definite ocular development. The gull-wing-like appearance of the stomodeum is still evident. C, Close-up of the maxillary median groove. The comma-shaped nasal pits do not exhibit the strong appearance of the major nasal prominences. D, Ventral view shows the breakdown of the buccal nasal membrane within the site of the primitive choanae (arrows). The newly formed lip of the maxilla can be seen containing a decreased maxillary median groove.

cumstances no ectoderm requires absorption; it is simply flat- advancing fusion there is merging of the mesoderm be- tened out in adaptation to the changed surface.7 tween the 2 prominences. This dynamically moves from the sill of the nose to the caudal margin of the lip. Streeter indicated that the furrow between merging Through the use of new investigative techniques, re- prominences became shallow and eventually smooth as the search into craniofacial development has led to the im- increase in mesoderm produced a new surface level. He hy- provement of theories previously hypothesized. The dis- pothesized that a cleft lip occurred when mesoderm failed covery of epidermal growth factors, cell adhesion molecules, to fill in the furrows and the epithelium broke down.7,8 and epithelial-mesenchymal transformation has provided Our study clearly demonstrates epithelial bridging mechanistic explanations of lip and palatal fusion.9 Sun et between prominences, which is inconsistent with Street- al10 found that in respect to the palate, the periderm of the er’s merging theory. The present study supports a new 2-layered embryonic epithelium sloughs prior to the pri- hypothesis of lip development, the “dynamic fusion mordial fusion, involving a cell adhesion molecule, cad- theory,” which acknowledges the fusion between promi- herin. The inner layer of the epithelium undergoes epithe- nences that are brought into opposition by the growing lial mesenchymal transformation.10 mesoderm. This is a dynamic process that begins Several processes of lip development and merging beneath the future sill of the nose. As the prominences prominences are well accounted for by the dynamic fu- grow, there is epithelial bridging and fusion. Behind this sion theory. With epithelial bridging and fusion there is

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Figure 7. Scanning electron microscopic views of stage 20 Macaca fascicularis embryo. A, This frontal view shows the developed nostril and the developed stomodeum. The stomodeum contains a smooth transition through the decreased maxillary median groove. B, In this oblique view, the ocular movement canbe seen relative to earlier stages. The developing auricle is visible caudal to the eye.

A B

Figure 8. Scanning electron microscopic views of stage 21 Macaca fascicularis embryo. A, The frontal view shows a definite humanlike appearance. The flattened maxillary median groove evens out the stomodeum. Major facial prominences have become less pronounced in visibility. B, The lateral view shows the medial movement of the developing eye as well as the developed nostrils.

not an exposed outward ridge of tissue. A nonaggrega- Although our study used a primate model, in com- tion of tissue suggests that programmed cell death or epi- paring the SEM photographs of human embryos taken thelial mesenchymal transformation occurs as epithe- by Hinrichsen,8 one is easily able to compare areas of po- lial cells close over other epithelial cells. Either process tential discrepancies. Two areas that have brought up would allow mesenchyme to develop under the newly questions across species are epithelial bridging and formed epithelial cells. Fusion must occur properly in fusion. The figures presented in Hinrichsen’s article both epithelial layers as well as the mesenchyme to avoid show fusion with evidence of programmed cell death and cleft deformities. In later stages when there is less vis- epithelial mesenchyme on histologic analysis. The SEM ible epithelial bridging, Streeter’s observation of epithe- figures also show epithelial bridging at stage 16, just as lial smoothing from mesenchymal ingrowth applies.7 our study shows. Hinrichsen’s work supports using non-

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Figure 9. Scanning electron microscopic views of stage 23 Macaca fascicularis embryo. The frontal (A) and lateral (B) views of a late stage 23 embryo show humanlike physical characteristics.

A B C

Figure 10. A drawing showing the contributions of the maxillary (orange), lateral nasal (purple), and medial nasal prominences (green) as an embryo and a child. A, Late stage 17 embryo; B, stage 18 embryo. In the developed young boy (C), the medial nasal prominence has produced the dorsal ridge of the nose, columella, and the lip philtrum. The ala of the nose has been created by the lateral nasal prominence. The cheeks and lateral upper lip have been created by the maxillary prominence. The lower lip and chin have been formed from the mandibular prominences.

human primates for studying the embryology of the lip Streeter and shown in the SEM photographs demonstrate and face.8 the mesenchymal merging process (Figure 5A). With fur- The dynamic fusion theory combines the mesoder- ther development and mesenchymal growth, the furrows mal contributions of the merging theory with epithelial fu- are smoothed out (Figure 6B). sion of the prominences. This dynamic fusion was likely The study of normal development of the lip can help difficult for Streeter to recognize with his best-fit 3-dimen- to elucidate abnormal growth. The major area of abnor- sional reconstruction method of studying embryologic de- mal lip development is in the form of clefts. The preva- velopment. Furthermore, the fusion is dynamic and oc- lent theory (Streeter’s merging theory) of lip develop- curs quickly (within 1-2 days) as the prominences of the ment tried to explain cleft formation by suggesting that lip develop. The paired labial furrows as described by without proper mesenchymal growth and support, the

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 epithelial layers would break down and a cleft would that challenges present theories and creates new form.7,11 The dynamic fusion theory requires reanalyz- hypotheses. The use of available nonhuman primate ing the etiology of cleft lips. Today we see 2 possible causes material has suggested a refinement of the mechanism of cleft lip anomalies: lack of epithelial/mesenchymal fu- by which the upper lip forms, which can be compared sion and mesenchymal hypoplasia. If epithelial fusion is with Streeter’s pioneering work on human embryos. blocked, a cleft will result. Through continued improvements in research tech- Mesenchymal growth may be the driving force niques, the dynamic fusion theory will be strengthened behind dynamic fusion. Without the mesenchyme or modified. pushing the 2 prominences together, there may be no need for epithelial fusion. Clinically, children with a Accepted for publication April 10, 2001. cleft lip often have some lack of mesenchymal tissue, This study was funded by grant RR 00169 from the but we cannot tell whether the cleft causes the lack of National Institutes of Health, Bethesda, Md. mesenchymal tissue or the lack of tissue causes the We would like to thank Laura Wilson for her SEM cleft. assistance. Specific facial features develop from distinct promi- Corresponding author and reprints: Craig W. Senders, nences (Figure 10). The lower lip develops from the fu- MD, 2521 Stockton Blvd, Suite 7200, Sacramento, CA 95817 sion of the mandibular prominences. The formation of the (e-mail: [email protected]). upper lip is formed from the maxillary prominence fusing medially with the paired medial nasal prominences REFERENCES (Figure 3C). The philtrum is formed from the fused paired medial nasal prominence. The vermilion, which is the tran- 1. O’Rahilly R, Muller F. Developmental Stages in Human Embryos. 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