Notch target genes in presomitic mesoderm cells have intrinisic oscilliatory expression

disrupt downstream regulation of genes that influence somitogenesis Mutations in Hes7 (Hes genes are transcriptional effectors of Notch signaling) disrupt downstream regulation of genes that influence somitogenesis

Differential adhesion and morphogenesis follow oscilliatory gene expression and signaling

A model for oscillatory signaling that divides the presomitic mesoderm into somites in a spatially and temporally ordered manner from anterior to posterior

1. Anterior expression domain of Mesp2 identifies next somite’s anterior boundary

2. Activated (NICD) notch and Lfng oscillate in register with Mesp2

3. Mesp2 regulates Notch activation via Delta regulation

4. Mesp2 protein oscillates to set posterior and anterior domains of Notch activation and thus define somite boundaries

3. Regulation of NICD via Lnfg is disrupted in Mesp2 null

the Mesp2 regulation of Lnfg may be direct 4. Mesp2 and NICD positively regulate Lnfg, and Hes7 provides negative feedback; the Mesp2 regulation of Lnfg may be direct

5. A model for the role of Mesp2 in regulating Notch activity via Dll1, Lnfg and Hes7

Somites are patterned locally to generate axial skeleton and muscalature

Somitic patterning depends upon signals from an increasingly complex set of local “organizers” …and these signals in turn activate locally distinct transcriptional programs

Somitic distinction of sclerotome and derma-myotome depends upon notochord-derived signals N-cadherin N-cadherin patterning disrupted locally ectopic notochord

Somitic patterning facilitates differentiation of all musculo-skeletal derivatives scleraxis

Myogenesis relies upon activation of distinct transcriptional program in myotome-derived myogenic precursors

Skeletogenesis requires cell migration from sclerotome followed by aggregation and local morphogenesis

Distinct network of local signals and transcriptional regulators defines skeletogenesis and differenttiates ti from myogenesis