splotch (Sp) mice as a model for WS1
The mouse Pax3 gene was identified as the gene responsible for splotch (Sp) mice. Sp mice exhibit a number of characteristic developmental anomalies which predominantly affect the neural tube and neural crest. Severe alleles in six types of homozygous Sp mice are fatal at the embryonic stage, and even splotch-retarded (Spd) mice, which have the least severe allele, encoding Pax3 with a substitution mutation at the paired domain, die at birth. Heterozygous Sp (Sp\/+) mice survive after birth and have white belly spots, but curiously, showed no sign of auditory defects; WS1 patients are usually heterozygous at the PAX3 gene and yet many show auditory dysfunction. The phenotype of Spd mice varies depending on their genetic background, suggesting the existence of modifier genes. It has been estimated that at least two genes interact with Spd to influence the craniofacial features.

microphthalmia (mi) mice as a model for WS2
Homozygous mi mice are microphthalmic due to the loss of retinal pigmentary epithelial (RPE) cells, white in coat color due to the loss of melanocytes, and deaf.
11 types of mi gene mutations, so far identified in mi mice, are transmitted in either a recesive or semi-dominant manner. In contrast, in humans is transmitted in a dominant manner.

Slugh-\/- mice as a model for WS2
Slugh-\/- mice have diluted coat color, a white forehead blaze, and areas of depigmentation on the ventral body, tail and feet. Hearing function has not yet been assessed in Slugh-\/- mice, but hyperactivity and circling behaviours observed in some Slugh-\/- mice suggest a vestibule-cochlear disorder.

WS4 mice as a model for WS4
Homozygous WS4 mice showed pigmentation anomaly (white coat color with black eye), aganglionic megacolon and cochlear disorder. Exons 2 and 3, which encode transmembrane domains III and IV of the Ednrb G-protein-coupled receptor protein, were deleted in these mice. Cochlea of WS4 mice showed endolymphatic collapse, due to the lack of melanocytes (intermediate cells) in the stria vascularis.

JF1 mice as a model for WS2
The JF1 mice are an inbred strain of mice derived from Japanese wild mice, which are often bred by Japanese laymen as fancy panda mice because of their cute appearance with black eyes and white spotting on a black coat. JF1 mice are not lethal even in the homozygous state. This non-lethality of JF1 mice is probably due to the fact that the mutation in mice is an insertional mutation in intron 1 that creates a cryptic splicing acceptor site that results in decreased expression of wild-type Ednrb but does not cause aganglionic megacolon. As JF1 mice have pigmentation anomalies and hearing impairment- but not megacolon or dysmorphogenesis- they constitute a mouse model of WS2. These notions are consistent with the finding that WS2 is occasionally caused by mutations in EDNRB.

lethal-spotted (ls) mice as a model for WS4
Homozygous mutations of the endothelin 3 (EDN3) gene cause coat spotting and aganglionic megacolon in ls mice and gene targeted edn3 null mice. Some of these mice can survive and mate; they are potentially a model for WS4, although cochlear disorders of these mice remain to be examined.

Dominant megacolon (Dom) mice as a model for WS4
The Sox10 gene is mutated in the dominant megacolon (Dom) mouse, an animal model of neurocristopathy, whose phenotype is reminiscent of Waardenburg-Hirschsprung patients. The pigmentary phenotype also suggests that Sox10 expression is essential for melanocyte development.
Homozygous Dom mice are lethal and their embryos lack neural crest-derived cells expressing the melanocyte lineage markers. Heterozygous Dom mice show white spotting and some of them show megacolon. Dom mice not respond to sound. They did not show endolymphatic collapse, suggesting that their stria vascularis had intermediate cells (melanocytes) sufficient for normal production of endolymph. However, their organ of Corti was missing.