Before detailing our classification scheme for candidate neurulation genes, four definitions are important to understand. A neurulation defect results in the formation of a neural tube defect (NTD) at the time of neurulation, and it occurs because the tissue and/or cellular basis of neurulation has been specifically disrupted within the tissues driving neurulation. Therefore, a neurulation gene is defined as one that causes a neurulation defect when mutated because it acts normally within the tissue(s) driving neurulation to generate neurulation-specific changes in cell behaviors. An NTD (see Inagaki et al., 2000) is defined as the abnormal development of the neural tube, occurring at any time prior to birth (i.e., at both neurulation and post-neurulation stages). A neurulation defect often results in an overt NTD at birth, but not necessarily so (restitution may occur during post-neurulation development). NTDs formed after normal closure of the neural groove are not neurulation defects by definition (i.e., they occur during post-neurulation development). An NTD gene is one that when inactivated results in an NTD. Neurulation genes are also NTD genes, but NTD genes are not necessarily neurulation genes.
The following classification of neurulation genes requires four levels of analysis. As a gene is assigned to progressively higher levels (in the + category), its candidacy as a neurulation gene strengthens. Genes excluded as neurulation genes at each level (assigned to the − category) are also interesting, because these genes may be NTD genes; they, like neurulation genes, are potential candidates for the causation of NTDs in humans, but they, unlike neurulation genes, do not normally influence the process of neurulation.
We list a total of 75 genes, with 20 genes implicated for the first time in a review as being involved in normal and abnormal neurulation (16s rRNA, Apaf1, Bcl10, Calr, Casp3, Casp9, Dpp6 (Kit), Efna5, Fdft1, Fkbp1a, Gas5, Ikk1+2, Jnk1+2, Nap1|2, Psen1+2, RhoGAP5, rnr-r1, Sil, Traf6, Zic2). From level 1 onward, we list the mouse genes whose loss of function (inactivated by targeted homologous recombination in mouse ES cells, by gene trap insertion or by classical mutations) is known, by the beginning of 2001, to cause neural tube defects, making them potential candidate neurulation genes. Note that some mutations only result in an NTD when they are combined with a loss-of-function mutation in another gene, either belonging to the same family (abl+arg, Jnk1+Jnk2, Itga3+Itga6, Ikk1+ Ikk2, Psen1+Psen2, Rara+Rarg) or to the same pathway (Enah+ Pfn1, Gap+Nf1, Xpc+Trp53). Other potential candidate neurulation genes are included because either they result in NTDs after other types of molecular perturbation (Dpp6, Gja1, Itgb1d, Notch3, Pax1, Zic3) or they have been identified on the basis of their expression in relevant tissues during neurulation (16s rRNA, Gas5, rnr-r1).
At level 2 and 3, we tried to determine, based on published phenotypes, whether the loss of gene function leads to a defect in the correct tissues at the time that neurulation is taking place, that is, to a neurulation defect. We consider a neurulation defect to be a specific defect that occurs in the mechanics of neurulation, that is, in processes such as changes in cell behavior, and/or the underlying mechanistic events that mediate these changes (e.g., changes in cytoskeleton or cell adhesion). These types of defects have been documented for D++ and XD++ genes. Inactivated genes that lead to alterations in the rate of cell cycle progression, cell division and programmed cell death at the time of neural groove closure may alter specifically the course and outcome of neural tube formation; therefore categories D++ and XD++ also include this type of gene (i.e., apoB, Bcl10, Folbp1, Ikk1+Ikk2, Psen1+Psen2 and Cart-1, Jnk1+ Jnk2, RBP-J kappa, c-ski, Tcfap2a, terc, respectively). Misregulation of cell number occurring after closure cannot be a neurulation defect (Casp3, Casp9, Apaf1, Nap1|2); the NTD in these mutations seems to result from neuroepithelial overgrowth/degeneration, subsequent to neurulation. Misregulation of neuronal specification, whatever its timing, is not considered as a neurulation defect because it is primarily a neurogenesis defect that causes an NTD (Atoh4, Hes1, Hoxa1, Ptch, Zic2). By definition, other non-neurulation defects include faulty neural tube development occurring after normal neurulation, such as the disruption or reopening of a previously normally closed tube (Hspg2), a spina bifida occulta (Pdgfra), late waviness in the neuroepithelium (TREB 5), etc. Some genes have been left in categories XD+ and D+ because it is unclear whether they affect neurulation specifically. This is especially true for the midline mutants Sil and Shh, which are known to cause a certain type of NTD, holoprosencephaly, which originated at the time of neurulation and at least in part in tissue involved in neurulation. Whether this phenotype is a neurulation defect and it demonstrates an instrumental role of the normal gene product in the morphogenesis of the neural plate into a tube is open to interpretation. A careful examination of level 4 criteria might help to make a definitive choice. Genes in category D+− have been shown, when mutated, to impede neurulation by an indirect defect (i.e., subsequent to another perturbation in early development that is necessary for normal neurulation, such as the growth or the axis formation of the embryo).
The best currently known candidate neurulation genes are those 16 level 3 XD++ mouse genes that are expressed at the right time and at the right place and when inactivated, result in a specific neurulation defect. A specific neurulation defect also results for 12 level 3 D++ genes when they are inactivated, although their pattern of expression is not consistent with a specific role in neurulation, revealing the susceptibility of this developmental process to defects in ubiquitous cellular processes, such as mitosis (Juriloff and Harris, 2000), or to conditions of placental insufficiency leading to malnutrition (apoB, Folbp1). It must be emphasized that the effect on neurulation of over expressing (gain of function; level 4) any of these 28 genes has not yet been studied.
Analysis of the Jnk1+Jnk2 double mutant provides the only well documented example of the physiological role of programmed cell death in neurulation. In contrast, transcriptional control of cytoskeletal dynamics specific to the neural plate is well documented (e.g., Enah, Macs, Mlp, RhoGAP5, shrm). The data from mutated mice are also beginning to reveal an integrin-dependent mechanism of neurulation, which is not surprising given the role of these molecules in epithelial morphogenesis and tissue integrity (De Arcangelis and Georges-Labouesse, 2000). The ephrin-A5 (Efna5) mutation results in the formation of anencephaly, presumably owing to the failure of the neural folds to fuse in the dorsal midline (Holmberg et al., 2000). Activation of ephrin-A5, induces changes in cell adhesion and cell morphology in an integrin-dependent manner (Davy and Robbins, 2000). Class A ephrins are tethered to the plasma membrane by a GPI anchor, giving at least one good reason why embryos mutant for the Pig-a gene (a gene involved in phosphatidylinositol glycan synthesis) have NTDs as well (Nozaki et al., 1999). Calr (possibly like Fkbp1a) is essential for the integrin-mediated flux of extracellular calcium (Shou et al., 1998; Rauch et al., 2000). Upon activation of neural adhesion molecules (especially integrin-dependent adhesion signaling), the action of PKC and the adhesion signaling molecule RhoGAP5 (Brouns et al., 2000) lead to a modulation of Rho GTPase activity, directing several actin-dependent morphogenetic processes within the neuroepithelium that are required for normal neurulation. Itga3 and Itga6 are prominent receptors for lama5 (i.e., laminin alpha5 chain; De Arcangelis et al., 1999). The Lama 5 mutation reveals the mechanical stress borne by the cranial neural folds (Miner et al., 1998). Lama 5 is the only neurulation gene documented to date that demonstrates an involvement in lateral extrinsic forces (i.e., in mutated embryos, there is a weakening of the lateral strip of epidermal ectoderm that decreases the amount of mediolateral force the ectoderm can generate on the neural fold).
Obviously, some candidate genes may need to be reclassified as additional data are obtained. With future better descriptions of the actual defects in neurulation caused by genetic modification, a better gene classification could be based on the type of tissue or cell behaviors affected. At present, such a classification is impossible.
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