Question

a. How would over-expression of BMP signaling proteins in the surface ectoderm adjacent to the developing neural tube affect the formation of the dorsolateral hinge points (DHLPs) b. Cells in the neural tube show an important change in the expression of cell adhesion proteins. What cell adhesion protein stops being produced and what is the effect on neural tube closure if this change does NOT occur?

Answer 1

Answer:

(a) Neural tube defects (NTDs) are among the most common types of lethal birth defects in the human population, second only to cardiovascular anomalies, occurring in approximately 1 in 1000 births worldwide. Anencephaly (failure in closure of the brain or skull vault) and spina bifida (closure defects in the spinal cord) are the most commonly occurring human NTDs. A successful approach for reducing the incidence of human NTDs is consumption of vitamin supplements, especially folic acid, by pregnant mothers; nevertheless, NTDs remain a serious human health problem.

The formation of the mammalian neural tube is an intricate morphogenetic process. The processes of neural induction and early embryonic morphogenesis result in the formation of the neural ectoderm, distinct from the surface ectoderm, overlying the notochord. Signals from the notochord, including Sonic hedgehog (Shh), induce a medially located floor plate in the neural ectoderm. The cells of the floor plate constrict at their apical ends, forming a medial hinge point for the initial furrowing of the neural tube (the neural groove).

Here we characterize the consequences of elevated bone morphogenetic protein (BMP) signaling on neural tube morphogenesis by analyzing mice lacking the BMP antagonist, Noggin. Noggin is expressed dorsally in the closing neural folds and ventrally in the notochord and somites. All Noggin−/− pups are born with lumbar spina bifida; depending on genetic background, they may also have exencephaly. The exencephaly is due to a primary failure of neurulation, resulting from a lack of mid/hindbrain dorsolateral hinge point (DLHP) formation. Thus, as previously shown for Shh signaling at spinal levels, BMP activity may inhibit cranial DLHP morphogenesis

(b) Further morphogenesis to create a closed neural tube occurs differently in different locations along the anterior–posterior (A–P) axis. In the future spinal cord, the neural tube closes dorsally in a “zippering” action, as the dorsal neural folds are brought into juxtaposition. The final step in formation of the closed neural tube is a change in adhesive properties as the cells of the lateral neural ectoderm/dorsal neural tube must release their contact with the adjacent surface ectoderm in favor of the apposing neural ectoderm to form a distinct, closed neural tube.

The formation of the cranial neural tube (future brain regions) is mechanistically different from closure of the caudal neural tube. In addition to the ventral medial hinge point, cells in the dorsolateral neural epithelium also form a hinge: the dorsolateral hinge points (DLHPs). The neural epithelium bends around the dorsolateral hinge points to come into direct apposition and form the closed cranial neural tube.

The BMP antagonist Noggin (Nog) is expressed in and around the neural tube, and embryos lacking Noggin show elevated BMP signaling in dorsal tissues during neurulation (Anderson et al., submitted for publication), demonstrating that Nog is an important regulator of BMP signaling in dorsal tissues. Nog−/− homozygotes die perinatally with spina bifida and exencephaly, along with severe defects in all skeletal elements. However, neither the specific nature of these phenotypes nor their developmental basis has been addressed.

Here, we analyze the mechanistic basis for the NTDs in Nog−/− embryos and assess the ability of nutritional supplements to rescue the mutant phenotypes. Our data indicate the exencephaly and spina bifida defects of Noggin mutants arise by distinct cellular and molecular mechanisms.

The exencephaly results from a failure of dorsolateral hinge point formation. In contrast, the spinal defects result from failure to maintain a closed neural tube due to defective paraxial mesoderm; these spinal defects are caused by increased BMP4 activity as a consequence of decreased BMP antagonism. Collectively, our studies reveal the roles of BMP antagonism in regulating closure of the neural tube in mammals. They also provide novel insight into the different morphogenetic causes that can underlie spinal and cranial neurulation defects.