Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation.

Abstract

We isolated a novel bHLH protein gene Mesp2 (for mesoderm posterior 2) that cross-hybridizes with Mespl expressed in the early mouse mesoderm. Mesp2 is expressed in the rostral presomitic mesoderm, but down-regulated immediately after the formation of the segmented somites. To determine the function of MesP2 protein (MesP2) in somitogenesis, we generated Mesp2.deficient mice by gene targeting. The homozygous Mesp2 (-/-) mice died shortly after birth and had fused vertebral columns and dorsal root ganglia, with impaired sclerotomal polarity. The earliest defect in the homozygous embryos was a lack of segmented somites. Their disruption of the metameric features, altered expression of Mox-1, Pax-l, and Dill, and lack of expression of Notchl, Notch2, and FGFR1 suggested that MesP2 controls sclerotomal polarity by regulating the signaling systems mediated by notch-delta and FGF, which are essential for segmentation.

Abnormal vertebral segmentation and the notch signaling pathway in man

“…If the carboxy-terminus in human MesP2 is required for transcriptional activation, then the mutant form of the protein described here, lacking the carboxyterminus, would lose this function. Mouse pups lacking MesP2 die within 20 minutes of birth, presenting with short tapered trunks and abnormal segmentation, affecting all but a few caudal (tail) vertebrae (Saga et al, 1997). This finding resembles Dll3-null mice, where the rib and vertebral architecture is disturbed along the entire axis.…”

“…The region between markers D15S117 and D15S1004 contains in excess of 50 genes and is syntenic to mouse chromosome 7 that contains the Mesp2 gene. The Mesp2 knockout mouse manifests altered rostrocaudal polarity, resulting in axial skeletal defects (Saga et al, 1997). The predicted human gene, MESP2, comprises two exons spanning approximately 2 kb of genomic DNA at 15q26.1.…”

“…A second site of Mesp expression is detected at 8.0 dpc immediately before somitogenesis. A pair of MesP-expressing bands appear on each side of the embryonic midline, at the anterior part of the PSM where the somites are anticipated to form (Saga et al, 1997(Saga et al, , 1999. During somitogenesis MesP1 and MesP2 continue to be expressed in single bilateral bands in the anterior PSM.…”

“…However, in the affected family the heterozygous parents demonstrated no axial skeletal defects, from which we deduce that this MESP2 mutation is recessive. Similarly, heterozygous mice are normal and fertile (Saga et al, 1997). It is possible that a single functional carboxy-terminus is sufficient to activate transcription but alternatively the MESP1 protein may compensate for the absence of MESP2 function, just as MesP1 can rescue the axial skeletal defects in MesP2-deficient mice in a dosage-dependent manner (Saga, 1998).…”

“…The extent to which this process directly correlates with somitogenesis in man is unknown, except that the phenotypes of the Mesp2 and Dll3 mutant mice bear a resemblance to human SCD (Saga et al, 1997;Kusumi et al, 1998;Dunwoodie et al, 2002). The findings in this one family provided the first evidence that MESP2 is critical for normal somitogenesis in man.…”