Distinct activities of Msx1 and Msx3 in dorsal neural tube development.
ABSTRACT Patterning of the dorsal neural tube involves Bmp signaling, which results in activation of multiple pathways leading to the formation of neural crest, roof plate and dorsal interneuron cell types. We show that constitutive activation of Bmp signaling at early stages (HH10-12) of chick neural tube development induces roof-plate cell fate, accompanied by an increase of programmed cell death and a repression of neuronal differentiation. These activities are mimicked by the overexpression of the homeodomain transcription factor Msx1, a factor known to be induced by Bmp signaling. By contrast, the closely related factor, Msx3, does not have these activities. At later stages of neural tube development (HH14-16), dorsal progenitor cells lose their competence to generate roof-plate cells in response to Bmp signaling and instead generate dorsal interneurons. This aspect of Bmp signaling is phenocopied by the overexpression of Msx3 but not Msx1. Taken together, these results suggest that these two different Msx family members can mediate distinct aspects of Bmp signaling during neural tube development.
Article: The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma.[show abstract] [hide abstract]
ABSTRACT: Neuroblastoma is an embryonal tumour of the peripheral sympathetic nervous system (SNS). One of the master regulator genes for peripheral SNS differentiation, the homeobox transcription factor PHOX2B, is mutated in familiar and sporadic neuroblastomas. Here we report that inducible expression of PHOX2B in the neuroblastoma cell line SJNB-8 down-regulates MSX1, a homeobox gene important for embryonic neural crest development. Inducible expression of MSX1 in SJNB-8 caused inhibition of both cell proliferation and colony formation in soft agar. Affymetrix micro-array and Northern blot analysis demonstrated that MSX1 strongly up-regulated the Delta-Notch pathway genes DLK1, NOTCH3, and HEY1. In addition, the proneural gene NEUROD1 was down-regulated. Western blot analysis showed that MSX1 induction caused cleavage of the NOTCH3 protein to its activated form, further confirming activation of the Delta-Notch pathway. These experiments describe for the first time regulation of the Delta-Notch pathway by MSX1, and connect these genes to the PHOX2B oncogene, indicative of a role in neuroblastoma biology. Affymetrix micro-array analysis of a neuroblastic tumour series consisting of neuroblastomas and the more benign ganglioneuromas showed that MSX1, NOTCH3 and HEY1 are more highly expressed in ganglioneuromas. This suggests a block in differentiation of these tumours at distinct developmental stages or lineages.Experimental Cell Research 03/2008; 314(4):707-19. · 3.58 Impact Factor
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ABSTRACT: Rhombomere 1 (r1), a temporary structure in the early developing brain, is bounded rostrally by the isthmus organizer and caudally by the r2 domain. Many genes involved in r1 induction and patterning have been identified. However, our knowledge of a comprehensive map of r1 regionalization defined by these genes at early embryonic stages remains fragmentary. In the present study, we examined the expression of a variety of genes in the dorsal r1 of E9.0-E10.5 mouse embryos. The expression domains within ventricular zone of these genes examined allowed us to define four distinct regions along the anterior-posterior (A-P) axis of the dorsal r1: the Wnt1/Lmx1a/Gdf7/Msx1/Msx2-positive roof plate, Math1/Olig3/Msx1/Msx2-positive, upper rhombic lip, Mash1/Ngn1/Ngn2-positive intermediate domain, and Mash1/Ngn1/Ngn2-positive rostral domain. Moreover, we defined the distribution of several genes expressed in the mantle zone of the dorsal r1, including Lmx1b, Lhx2, Lhx9, Phox2a and Phox2b. Taken together, our gene expression data identify a refined subdivision of the dorsal r1 with four distinct domains along the A-P axis and a mantle zone at early embryonic stages.Brain research bulletin 03/2010; 82(1-2):74-82. · 2.18 Impact Factor
Article: Conservation, development, and function of a cement gland-like structure in the fish Astyanax mexicanus.[show abstract] [hide abstract]
ABSTRACT: The larvae of the fish Astyanax mexicanus transiently develop a flat and adhesive structure on the top of their heads that we have called "the casquette" (cas, meaning "hat"). We hypothesized that the cas may be a teleostean homolog of the well-studied Xenopus cement gland, despite their different positions and structures. Here we show that the cas has an ectodermal origin, secretes mucus, expresses bone morphogenic protein 4 (Bmp4) and pituitary homeobox 1/2 (Pitx1/2), is innervated by the trigeminal ganglion and serotonergic raphe neurons, and has a role in the control and the development of the larval swimming behavior. These developmental, connectivity, and behavioral functional data support a level of deep homology between the frog cement gland and the Astyanax cas and suggest that attachment organs can develop in varied positions on the head ectoderm by recruitment of a Bmp4-dependent developmental module. We also show that the attachment organs of the cichlid Tilapia mariae larvae display some of these features. We discuss the possibility that these highly diversified attachment glands may be ancestral to chordates and have been lost repetitively in many vertebrate classes.Proceedings of the National Academy of Sciences 10/2010; 107(40):17256-61. · 9.68 Impact Factor