Transcriptional and signaling regulation in neural crest stem cell-derived melanocyte development: do all roads lead to Mitf?

REVIEW Ling Hou and William J Pavan npg Cell Research (2008) 18:1163-1176. 1163 npg © 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/08 $ 30.00 www.nature.com/cr Transcriptional and signaling regulation in neural crest stem cell-derived melanocyte development: do all roads lead to Mitf? Ling Hou1 , William J Pavan2 Developmental Cell Biology and Disease Program, State Key Laboratory Cultivation Base and Key Laboratory of Vision Science of China Ministry of Health, Eye Hospital, Wenzhou Medical College, 270 Xueyuan Road, Wenzhou, Zhejiang 325003, China; 2Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA 1 Human neurocristopathies include a number of syndromes, tumors, and dysmorphologies of neural crest (NC) stem cell derivatives. In recent years, many white spotting genes have been associated with hypopigmentary disorders and deafness in neurocristopathies resulting from NC stem cell-derived melanocyte deficiency during development. These include PAX3, SOX10, MITF, SNAI2, EDNRB, EDN3, KIT, and KITL. Recent studies have revealed surprising new insights into a central role of MITF in the complex network of interacting genes in melanocyte development. In this perspective, we provide an overview of some of the current findings and explore complex functional roles of these genes during NC stem cell-derived melanocyte development. Keywords: neurocristopathy, Waardenburg syndrome, white spotting mice, pigment cells, differentiation Cell Research 18:1163-1176. doi: 10.1038/cr.2008.303; published online 11 November 2008 Neural crest stem cell development The neural crest (NC) is a unique embryonic structure and contains a remarkable multipotent stem cell population that arises during vertebrate embryogenesis [1, 2]. NC has been referred to as the fourth germ layer because of its great importance during development [3]. NC stem cells arise from the dorsal neural tube during neurolation in early development, then migrate out from the neural tube and along defined pathways throughout the body, where they contribute to numerous cell types and tissues, including melanocytes, ocular and periocular structures, bone and cartilage cells of the cranial skeleton, odontoblasts, autonomic neurons, sensory neurons, enteric neurons, smooth muscle, endocrine cells, chromaffin cells, and glial cells [1]. Although it has long been thought that the fates of NC-derived lineages are controlled by transcription and growth factors, the physiological functions of these factors are not fully known. Understanding NC development is medically important Correspondence: Ling Hou Tel: +86-577-88067931; Fax: +86-577-88824115 E-mail: www.cell-research.com | Cell Research because defective derivatives of aberrant NC cell development give rise to numerous human diseases known as neurocristopathies [4]. These diseases include ocular diseases (such as iris hypoplasia and optic nerve head melanocytoma), cardiocutaneous syndromes, craniofacial malformations of mesoectodermal origin, DiGeorge syndrome, Ewing’s tumors, Hirschsprung disease, lentigo, medullary carcinoma of the thyroid, melanotic nevi, melanoma, multiple endocrine neoplasia (types 2A and 2B), neuroblastoma, neurocutaneous syndromes, neurofibromatosis type 1, PCWH (Peripheral demyelinating neuropathy, Central dysmyelinating leukodystrophy, Waardenburg syndrome (WS), and Hirschsprung disease), PHACES syndrome (Posterior fossa abnormalities and other structural brain abnormalities, Hemangioma(s) of the cervical facial region, Arterial cerebrovascular anomalies, Cardiac defects, aortic coarctation and other aortic abnormalities, Eye Anomalies, Sternal defects, and/or Supraumbilical raphe), pheochromocytoma, piebaldism, WS, Tietz syndrome, and more [4]. Among these WS is an autosomal-dominant subtype of complex NC diseases and is named after the Dutch ophthalmologist who, in 1947, first described a patient with heterochromia iridis (different eye colors), congenital deafness, and dystopia canthorum (lateral displacement of the inner canthi of the eyes leading to a wide nasal bridge). npg Regulation of melanocyte development 1164 WS patients also show additional defects, including white forelock, pigmentary disturbance of the skin, upper limb abnormalities, and megacolon [5]. To date there are at least four types of WS that are due to mutations in separate transcription factors, including SOX10, MITF, PAX3, and SNAI2, and in signaling molecules, including EDNRB and EDN3. The four WS types are categorized based on presentation of various subsets of the phenotypic characteristics of the syndrome. For example, WS type 1 patients have craniofacial defects, WS type 3 patients have craniofacial and limb defects, and WS type 4 patients have megacolon. Intriguingly, distinct subtypes of WS and piebaldism, which is associated with mutation of KIT, often have the common phenotype of hypopigmentation, which is due to melanocyte defects in the skin. The comparable hypopigmentation defect in these diseases reflects a possible functional relationship among the disease-associated genes in melanocyte development. In this review, we discuss the known functional roles of these genes during NC stem cellderived melanocyte development and propose alternative models of functional roles of these genes, with a focus on the central role of MITF. White spotting mouse disease models and melanocyte development Gene expression programs that direct the development of distinct cell lineages from unspecified precursor cells are the result of complex interactions between cell-extrinsic signals and transcription factors. An excellent system to study such interactions is provided by the development of melanocytes. Their precursor cells, the melanoblasts, originate from multipotent NC stem cells and migrate along characteristic pathways to various destinations such as the iris and the choroid of the eye, the inner ear, the dermis, and the epidermis. In the skin, these precursors differentiate into melanin-producing cells that determine skin color and protect the organism from UV radiation, one of the risk factors for skin cancers such as melanoma [6]. In addition, the precursors distribute into the bulged region of developing hair follicles, where they persist as selfrenewing stem cells in the niche [7]. For their development, melanoblasts depend on numerous transcription factors and signaling systems. These include the transcription factors PAX3 [8, 9], SOX10 [9-11], and MITF (Microphthalmiaassociated Transcription Factor) [12], the WNT signaling pathway [13, 14], G protein-coupled endothelin receptor B (EDNRB) and its ligand, endothelin 3 (EDN3) [15, 16], and receptor tyrosine kinase KIT and KIT-ligand (KITL) [17, 18]. Among the genes encoding these factors, Mitf, Sox10, Pax3, Kit, and Kitl comprise a particularly intriguing set, since heterozygosity for certain mutations in each of these genes (...truncated)