Disease relevance of Zeb2

• Here, we show that Zfhx1b-knockout mice do not develop postotic vagal neural crest cells, the precursors of the enteric nervous system that is affected in patients with Hirschsprung disease, and they display a delamination arrest of cranial neural crest cells, which form the skeletomuscular elements of the vertebrate head [1].
• Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy [2].

High impact information on Zeb2

• Mice lacking ZFHX1B, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome [1].
• SIP1 encodes Smad interacting protein 1, a new member of the delta EF1/Zfh-1 family of two-handed zinc finger/homeodomain transcription factors [3].
• SIP1, among other functions, seems to play crucial roles in normal embryonic development of neural structures and neural crest [3].
• In a first attempt to address this issue we have investigated the Smn interacting protein 1 (Sip1), with an emphasis on its developmental expression and subcellular distribution in spinal motor neurons in relation to Smn [2].
• Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing early truncation of the protein [3].

Biological context of Zeb2

• Organization of the mouse Zfhx1b gene encoding the two-handed zinc finger repressor Smad-interacting protein-1 [4].
• Both of the proteins bind to a bipartite CACCT/CACCTG DNA sequence, but only Sip 1 can interact with activated SMAD proteins in vitro [5].
• Taken together, these results offer an intriguing possibility that ALP up-regulation at the onset of BMP-induced osteogenesis could involve Smad/SIP1 interactions, resulting in the derepression of that gene [6].
• Therefore, SIP1, like deltaEF1, is likely to be a transcriptional repressor, which may be involved in the regulation of at least one immediate response gene for activin-dependent signal transduction pathways [7].
• Sip1, a Smad-binding zinc-finger homeodomain transcription factor, has essential functions in embryonic development, but its role in individual tissues and the significance of its interaction with Smad proteins have not been fully characterized [8].

Anatomical context of Zeb2

• Zfhx1b, in contrast, was present in a broad area around developing tendon and partially overlapping with the expression of genes associated with myogenic differentiation [5].
• Involvement of SIP1 in positioning of somite boundaries in the mouse embryo [9].
• This caused the development of a small hollow lens connected to the surface ectoderm, identifying two Sip1-dependent steps in lens development [8].
• In the lens lineage, Sip1 expression is activated after lens placode induction, and as the lens develops, the expression is localized in the lens epithelium and bow region where immature lens fibers reside [8].
• Sip1 is highly expressed in the spinal cord during early development and expression decreases in parallel with Smn during postnatal development [2].

Other interactions of Zeb2

• Zfhx1a and Zfhx1b mRNAs have non-overlapping expression domains during chick and mouse midgestation limb development [5].
• Regulation of ocular lens development by Smad-interacting protein 1 involving Foxe3 activation [8].
• In this paper, we investigate the function of Smicl, a zinc-finger Smad-interacting protein that is expressed maternally in the Xenopus embryo [10].

References