|For the Sp series:|
|Gene (MGI)||All Alleles (MGI)|
Five mutations, all of which occurred at the Jackson Laboratory, have been noted for this locus on the first chromosome ( Snell et al., 1954; Parsons, 1958). Four of these are presumed to be mutations to splotch ( Sp) and the other to a second allele, delayed splotch ( Spd) ( W. Russell, 1947; Dickie, 1964b). Both alleles are semidominant and lethal when homozygous.
|For the Sp allele:|
|Sp Allele (MGI)||Gene (MGI)||All Alleles (MGI)|
The first mutation to Sp occurred in the C57BL strain and was described by W. Russell ( 1947). Heterozygotes ( Sp/+) display white spotting on the belly and occasionally on the back, feet, and tail. 24 Sp/Sp embryos usually die at 13 days of gestation ( Auerbach, 1954) 25 with multiple abnormalities. 26 These have been described in detail by Auerbach ( 1954) and the following is based on his account (see also Hsu and van Dyke, 1948).
Sp/Sp embryos can first be recognized at 9 - 9.5 days of gestation by the fact that in contrast to the virtually completely closed neural folds of normal embryos, their neural folds are open in the region of the hind limbs and there is an aggregation of neural tissue on either side of the dorsal midline. This development of open neural folds and of neural overgrowth (which is known as rachischisis) is variable but usually is confined to a discrete area of the lumbosacral region. The degree of neural outgrowth in the region of the rachischisis may be relatively slight or quite excessive. Indeed, by the twelfth day of gestation the "overgrowth of neural tissue may manifest itself by large flaps of tissue projecting laterally from the embryo."
In addition to this abnormality, just over half of Sp/Sp embryos 10 days or older display open neural folds of the head region (cranioschisis). The condition is limited to the region of the hind brain (the myelencephalon and rhombencephalon) and is invariably associated with outgrowth of neural tissue. The lumen of the brain of homozygous Sp embryos is also highly distorted throughout, being partially collapsed or obliterated by the irregular and excessive growth of neural tissue."
Although the neural tube abnormalities are most pronounced in the lumbosacral and cranial regions they are not confined to these areas as the neural tube displays some degree of malformation throughout its length. While its pathway is straight in normal embryos, in splotch homozygotes it "weaves more or less erratically and is collapsed at irregular intervals throughout the embryo."
Splotch homozygotes also are characterized by abnormalities of the dorsal root ganglia and, in some cases, the sympathetic ganglia. Tail abnormalities also occur. These may be recognized in 10-day-old embryos and include a wide variety of morphological distortions.
In view of the fact that the presence of one Sp gene produces white spotting, it was of interest to determine how this mutation would affect pigmentation when homozygous. This was achieved by transplanting tissue from 9.5- to 12.5-day old Sp/Sp embryos to either the coelom of chick embryos or to the anterior chamber of adult albino mouse eyes. The tissue implanted from 11.5-day-old or older embryos was comprised of ectoderm and underlying mesoderm, whereas neural crest and somite material were also included in grafts from younger embryos. Similar implants from +/+ and Sp/+ embryos served as controls ( Auerbach, 1954).
Auerbach found that these grafts, which were allowed to develop in their new environments for 16 days, developed pigment only when derived from normal ( Sp/+ or +/+) embryos. Thus no trace of pigment was found in either the implant or the surrounding tissue when it originated from an Sp/Sp embryo, even though in many cases numerous (unpigmented) hairs were present. These findings indicate that splotch when homozygous results in a complete failure to produce functioning melanocytes. In this regard the effect of Sp parallels the effect of dominant spotting ( W); one dose of either of these genes is associated with white spotting, whereas two doses eliminates all pigment save that of the retina which is normal. This of course is not surprising since, as noted previously ( Chapter 1, note 5), the pigmented cells of the retina are not of neural crest origin.
It thus appears that the splotch syndrome is due to a disturbance of the region of the embryo which includes the neural crest and the dorsal part of the neural tube, and that as a result of this disturbance Sp homozygotes do not produce any viable melanoblast clones.
|For the Spd allele:|
|Spd Allele (MGI)||Gene (MGI)||All Alleles (MGI)|
Three other apparent mutations to splotch have been reported by Dickie ( 1964b). Two of these ( SpJ and Sp3J) occurred in C57BL/6 males and the other ( Sp2J) in a C3H/HeJ female. 27
Dickie reported two other semidominant mutations which were lethal when homozygous and one of these proved to be another splotch locus allele. 28 This allele also occurred in C57BL/6J and is called "delayed splotch" ( Spd) because homozygotes are not as severely malformed and their death is delayed in comparison with Sp homozygotes. Spd/+ mice have a large belly spot. Spd/Spd homozygotes survive until birth and although they consistently suffer from caudal rachischisis in no case has any gross anomaly in the anterior portions of the fetus been observed. Sp/Spd heterozygotes are lethal and similar in appearance to Spd homozygotes. Linkage studies have provided further evidence that Sp and Spd are alleles ( Dickie, 1964b).