Developmental Biology and Morphogenesis of the Face, Lip And

Developmental Biology and Morphogenesis of the Face, 1 Lip and Palate Alphonse R. Burdi Prologue. The “history of man for the nine months preceding his birth would, probably, be far more interesting and contain events of greater moment than all the three score and ten years that follow it.” Samuel Taylor Coleridge, Miscellanies, Aesthetic and Literary. Circa 1800. The developmental biology of the face, lip, and palate active behaviors at intracellular, cell surface, and ex- is best understood against a backdrop of biological tracellular matrix levels. Complete or partial inter- paradigms and information drawn from the multidis- ruptions of any one or combination of these phenom- ciplinary worlds of classical embryology, develop- ena have been implicated in the identification of mental biology, and, today, from the exciting world of etiologic and pathogenic causes of mammalian birth molecular biology.The advent of many new and excit- defects, including those of the human craniofacial ing clinical interventional strategies for the treatment regions. of birth defects now allows the clinician to treat the Normal and abnormal morphogenesis of the cran- most delicate of craniofacial abnormalities which iofacial regions, and even that of rest of the body, is were beyond the realm of treatment even for the skill- dependent upon a myriad of cell types and tissues. ful clinician due to lack of appropriate technologies. One of the most important cell types in understand- Even the details of craniofacial morphogenesis, how- ing normal and abnormal craniofacial morphogene- ever interesting to the clinician, were also seen as be- sis is the neural crest cell [2,36].While the importance ing beyond the everyday clinical realm, or esoteric, of crest cells has been hypothesized for a century or prior to the advent of the new wave clinical interven- more, not until the advent of neural crest biological tional techniques, such as high resolution imaging markers – first with isotopic labels and later with spe- and information technologies, in the fields of cranio- cific markers as monoclonal antibodies, intracellular facial and maxillofacial surgery. Today, there is a dyes, and protein assays – did the neural crest become rekindled need to understand more of the details of so widely appreciated in a variety of studies of verte- craniofacial morphogenesis, especially as that under- brate embryogenesis in general, and human craniofa- standing increases our awareness of the etiology, cial morphogenesis, in specific. While the majority of pathogenesis, and clinical features of a variety of recent neural crest studies of have necessarily dealt craniofacial defects. The goal of this chapter is to pro- with chick and mouse embryos, there is ample evi- vide a highlighted update or working understanding dence to show that basic information and associated of the “developmental blueprint” followed in human technologies gained from vertebrate embryos can be craniofacial morphogenesis, with a special focus on directly applied to neural crest cells in mammalian defects of the face, lip, palate, and associated struc- and human embryos. tures. With this in mind, prime consideration should be While recent advances in developmental and mo- given to neural crest cells because they contribute lecular craniofacial biology contribute heavily to the heavily to craniofacial morphogenesis. These impor- picture of face and palate morphogenesis, there has tant “building-block” cells arise from the final stages been an explosion in our fundamental understanding in formation of the embryonic neural tube. Neural of the very beginnings of these body regions [43]. crest cell specificity is the result of an inductive action Such new information clearly centers on the genesis, by nonneural ectoderm adjacent to the developing behavior, and developmental outcomes of many cran- neural tube (mediated by bone morphogenetic pro- iofacial “building block “ cell types throughout their teins BMP-4 and BMP-7) on the lateral cells of the life span. These fundamental phenomena include pat- neural plate as the plate transforms from a plate of ec- terns of early DNA signaling, gene and biochemical toderm into the definitive neural tube. The induced organizers,nuclear and cellular differentiation,prolif- neural crest cells express the transcription factor slug eration,migration,and,importantly,patterns of inter- which characterizes cells which separate from an em- 4 A.R. Burdi bryonic epithelial layer and subsequently migrate as from lower cervical to the most caudal embryonic mesenchymal cells away from the parent site [33]. somites in humans. Trunk neural crest cells appear to The identification of the exact molecular mecha- have lessened migratory pathways and have fewer de- nisms and cellular events linked to the differentiation, velopmental outcomes than cranial neural crest cells, proliferation and, and especially, of the migration of including formation of spinal ganglia, sympathetic crest cells into the facial and pharyngeal regions is not ganglia, and adrenal medulla chromaffin cells. Inter- yet fully known.What is known, however, is that, with estingly, unlike cranial crest cells, trunk neural crest the variant OTX2 transcription factor, specific pat- cells do not have the capacity to differentiate into terns of neural crest proliferation and migration into skeletal tissues. the pharyngeal arches are controlled by four members The life history of cranial neural crest cells, while of homeodomain proteins called HOX genes (A-D). not of any more importance than trunk neural crest Another factor thought to be critical in the migration cells,appears to be more complex.Cranial neural crest of crest cells is a loss of cell-to-cell adhesiveness which cells are a major component of the embryo’s cephalic is associated with the loss of cell adhesion molecules end and differentiate into a wide variety of cell and (CAMs) characteristic of the neural tube and the mi- tissue types, including connective, skeletal, dentin, grating neural crest cells [91]. Following the comple- and muscle tissues of the face [64]. Unlike trunk neu- tion of craniofacial crest cell migrations and differen- ral crest cells,which show diffuse migratory pathways, tiation into specific structures (such as bones of the cranial neural crest cells follow specific migratory facial skeleton) CAMs are re-expressed. Migrating pathways into specific regions of the embryonic head. craniofacial crest cells are thought to travel through They arise from the more cephalic neural tube regions cell-free intercellular spaces and pathways that have and migrate ventrally into the pharyngeal arches ad- high levels of extracellular matrix molecules [3, 9, 10]. jacent to the upper regions of the embryonic gut tube. These migrations are determined by factors intrinsic Such migrations are extensive and follow very definite to the crest cells themselves and features of the exter- migratory paths away from the neural tube and into nal environment through which the crest cells mi- the facial and pharyngeal regions. In hindbrain re- grate. While most available information on neural gions,neural crest cells arise from eight segmented re- crest migratory pathways comes from chick studies, gions on either side of the hindbrain (rhomben- data suggest that such information is applicable to cephalon) called rhombomeres (numbered R1-R8) mammalian and humans as well. Migrations are facil- and subsequently migrate into specific pharyngeal itated by the presence of such molecular substrates as arches [12, 14]. fibronectin, laminin, and type IV collagen. Attach- Crest cells from R1 and R2 centers migrate into the ment to and migration of crest cells is mediated by a first pharyngeal arch and play important roles in the family of attachment proteins called integrins.It is im- formation of Meckel’s cartilage and the malleus and portant to note that other extracellular matrix mole- incus ear ossicles developing from it. Crest cells from cules in the pathway (e.g., chondroitin sulfate-rich R4 migrate into the second arch and contribute to the proteoglycans) can impede or block the normal mi- formation of the stapes, styloid process, and lesser gration of neural crest cells, which may lead to a num- horn of the hyoid bone.Crest cells from R6 and R7 mi- ber of craniofacial malformations. grate into the third arch, and those from R8 migrate As will be expanded upon later in this chapter,neu- into the fourth and sixth pharyngeal arches. The one ral crest cells have the remarkable capacity to differ- variant noted above is that the first pharyngeal arch entiate into a wide variety of anatomical structures also includes crest cells from midbrain levels which throughout the body. Exactly what controls crest dif- express OTX2 transcription factors. Little evidence ferentiation is still an open question. One hypothesis exists to show that crest cells from rhombomeric cen- is that all neural crest cells are equal in their develop- ters R3 and R5 play any significant role in human mental potential, and their ultimate differentiation is craniofacial morphogenesis. Crest cells initially ex- entirely predetermined by the environment through press the HOX genes from their originating rhom- which the crest cells migrate and finally reside, i.e., bomeric center, but maintenance of a specific expres- “extrinsic determinants.” A second hypothesis favors sion is dependent upon interaction of the crest cells “intrinsic determinants” and suggests that premigra- with the arch-specific

Load more