The Dkk1 dose is critical for eye development.

During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via ß-catenin mediated Pdgfrα and E-cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects.

Cecr2 mutations causing exencephaly trigger misregulation of mesenchymal/ectodermal transcription factors.

BACKGROUND: Over 200 mouse genes are associated with neural tube defects (NTDs), including Cecr2, the bromodomain-containing subunit of the CERF chromatin remodeling complex. METHODS: Gene-trap mutation Cecr2(Gt45Bic) results in 74% exencephaly (equivalent of human anencephaly) on the BALB/c strain. Gene expression altered during cranial neural tube closure by the Cecr2 mutation was identified through microarray analysis of 11-14 somites stage Cecr2(Gt45Bic)embryos. RESULTS: Analysis of Affymetrix Mouse 430 2.0 chips detected 60 transcripts up-regulated and 54 transcripts down-regulated in the Cecr2(Gt45Bic) embryos (fold > 1.5, p < 0.05). The Cecr2 transcript was reduced only approximately 7- to 14-fold from normal levels, suggesting the Cecr2(Gt45Bic) is a hypomorphic mutation. We therefore generated a novel Cecr2 null allele (Cecr2 (tm1.1Hemc)). Resulting mutants displayed a stronger penetrance of exencephaly than Cecr2(Gt45Bic) in both BALB/c and FVB/N strains, in addition to midline facial clefts and forebrain encephalocele in the FVB/N strain. The Cecr2 transcript is reduced 260-fold in the Cecr2(tm1.1Hemc) line. Subsequent qRT-PCR using Cecr2 (tm1.1Hemc) mutant heads confirmed downregulation of transcription factors Alx1/Cart1, Dlx5, Eya1, and Six1. CONCLUSIONS: As both Alx1/Cart1 and Dlx5 mouse mutations result in exencephaly, we hypothesize that changes in expression of these mesenchymal/ectodermal transcription factors may contribute to NTDs associated with Cecr2.

Hereditary hair loss and the ancient signaling pathways that regulate ectodermal appendage formation.

All epidermal appendages, including hair, teeth, and nails, begin as a thickening of the ectoderm, called a placode. The placode arises from a primary induction signal that is sent from the underlying mesenchyme to the overlying epidermis. In mammals, the precise arrangement of hair follicles in the skin is due to the amount and distribution of signals that promote and inhibit hair placode formation. Continued development of a hair follicle after placode formation requires a complex cross-talk between the mesenchyme and epidermis. Here, I will review recent studies in humans and mice that have increased our understanding of the role of these signaling pathways in normal development and in hereditary hair loss syndromes. The study of normal hair development may suggest ways to restore or eliminate hair and might identify possible targets for the therapy of basal cell carcinoma, a cancer which strongly resembles embryonic hair follicles.

Histogenetic and neoplastic potential of different regions of the mouse embryonic egg cylinder.

The histogenetic and neoplastic potentials of defined regions of the 8th day mouse embryonic egg cylinder were examined following ectopic transfer to beneath the testis capsule. No differences in histogenetic potential were detected between anterior and posterior slices of the embryo, either when composed of all three germ layers or of embryonic ectoderm alone. Small anterior and distal fragments of embryonic ectoderm also produced similar histogenetic profiles, although posterior fragments failed to grow in this ectopic site. The histogenetic potential of anterior and distal fragments exceeded the developmental fate ascribed to these two regions in the embryo (Beddington, 1981). There was some evidence for regionalization with respect to neoplastic potential, anterior slices of the embryo giving rise to a higher incidence of embryonal carcinoma cells than posterior slices.