Biological Function of the Murine Zic Genes

Overview of Rodent Zic Genes

10.6 Biological Function of the Murine Zic Genes

Mutation and phenotype analysis of the murine Zic genes provides one of the most comprehensive insights into Zic gene function. As can be seen from Table 10.2, multiple alleles for each of the murine Zic genes exist and have been produced from a variety of mutagenesis strategies. The majority of alleles, however, are severe loss- of- function with partial loss-of-function alleles (aka hypomorphic alleles) available only for Zic2. Moreover, Zic3 is the only gene for which a conditional allele is avail- able. Together this means that for many of the genes, the available alleles are pri- marily useful for studying the earliest function of that gene. Despite this, the analysis of these alleles has yielded an extensive list of processes, tissues and organs that require the function of one or more murine Zic genes for normal development.

Processes affected by the absence of Zic gene function include axis formation, as well as the patterning and morphogenesis of the central nervous, visual, musculo- skeletal and vascular systems (Table 10.3). Mutation of the murine Zic genes gives rise to the same conditions associated with Zic gene loss-of-function in humans.

The phenotypic consequences of Zic gene loss-of-function have been summarized before (Houtmeyers et al. 2013), and many are covered in depth in other chapters of this book. Here, we review some features of Zic gene and ZIC protein activity that emerge when one considers the combined information from Zic gene phenotyping studies.

10.6.1 Redundant Zic Gene Function

Genetic redundancy means that two or more genes are performing the same func- tion and that inactivation of one gene has little or no effect on the biological pheno- type. Full functional redundancy is demonstrated when single mutants have no phenotype but the double mutant does. In contrast, partial redundancy is said to occur when one or both of the single mutants exhibits a phenotype that is enhanced

K. E. M. Diamand et al.

Table 10.2Murine Zic alleles MGI allele IDAllele symbolAllele nameSynonymsAllele typeAllele attributesHuman disease modelsReferences Zic1Roderick (1983) MGI:3789699In(9)26RkInversionIn26RkCIAruga et al. (2002b) MGI:3759860Tg(Zic1,- lacZ)1JaruTransgene insertion 1Z19KTrInserted expressed sequenceAruga et al. (2002b) MGI:3759865Tg(Zic1tr,- lacZ)1JaruTransgene insertion 1TR9KTrInserted expressed sequenceAruga et al. (2002b) MGI:3510680Zic1/Zic4tm1KjmiTargeted mutation 1Zic1−Zic4−TNullDandy-Walker syndromeGrinberg et al. (2004) MGI:2156822Zic1tm1JaruTargeted mutation 1TNullJoubert syndromeAruga et al. (1998) Zic2 MGI:5566852Zic2em1BendEndonuclease-mediated mutation 1BL6–1ENullDavies et al. (2013) MGI:5566853Zic2em2BendEndonuclease-mediated mutation 2C3H-5ENullDavies et al. (2013) MGI:5566854Zic2em3BendEndonuclease-mediated mutation 3C3H-8ENullDavies et al. (2013) MGI:5566855Zic2em4BendEndonuclease-mediated mutation 4C3H-10ENullDavies et al. (2013) MGI:5566856Zic2em5BendEndonuclease-mediated mutation 5C3H-19ENullDavies et al. (2013) MGI:1862004Zic2KuKumbaGena29, KuENUHoloprosencephalyBrown et al. (2000) MGI:4943187Zic2m1NiswMutation 1Line7–12ENUHypomorphZhang and Niswander (2013) MGI:2156825Zic2tm1JaruTargeted mutation 1Zic2KdTHypomorphHoloprosencephaly, schizophreniaNagai et al. (2000) (continued)

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Table 10.2(continued) MGI allele IDAllele symbolAllele nameSynonymsAllele typeAllele attributesHuman disease modelsReferences Zic3 MGI:1856679Zic3BnBent-tailBnSHeterotaxyGarber (1952) MGI:3043028Zic3KaKatunKaSHeterotaxyBogani et al. (2004) MGI:5476827Zic3tm1.1SmwaTargeted mutation 1.1Zic3floxTSutherland et al. (2013) MGI:2180720Zic3tm1BcaTargeted mutation 1Zic3−, Zic3nullTNullHeterotaxyPurandare et al. (2002) MGI:3698161Zic3tm1JwbTargeted mutation 1Zic3neo, Zic3nullTNullGoldenhar syndromeZhu et al. (2007) MGI:5470150Zic3tm2.1JwbTargeted mutation 2.1Zic3floxTNo functional changeJiang et al. (2013) Zic4 MGI:3789699In(9)26RkInversionIn26RkCIRoderick (1983) MGI:3510681Zic1/Zic4tm1KjmiTargeted mutation 1Zic1−Zic4−TNullDandy-Walker syndromeGrinberg et al. (2004) MGI:3510678Zic4tm2KjmiTargeted mutation 2Zic4−TNullGrinberg et al. (2004) Zic5 MGI:3052154Zic5tm1JaruTargeted mutation 1DeltaneoTNullInoue et al. (2004) MGI:3574814Zic5tm1SiaTargeted mutation 1Opr−TNullFurushima et al. (2005) Tr transgenic, T targeted, E endonuclease-mediated, CI chemically induced (non-ENU), S spontaneous

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Table 10.3 Murine Zic loss-of-function phenotypes

Zic phenotypes Genotypes References

Gastrulation Primitive streak dysgenesis

Zic3^/−, Zic3^−/Y Ware et al. (2006) Failure of anterior

notochord production Zic2^Ku/Ku Warr et al. (2008)

Left-right axis defects Zic2^Ku/Ku Carrel et al. (2000), Purandare et al.

(2002), Ahmed et al. (2013), and Barratt et al. (2014)

Zic3^Bn/Bn, Zic3^Bn/Y, Zic3^Bn/+, Zic3^−/−, Zic3^−/Y

Zic3^Ka/Ka, Zic3^Ka/Y

Node cilia defects Zic2^Ku/Ku Barratt et al. (2014) Patterning and morphogenesis

Exencephaly Zic2^Ku/Ku, Zic2^kd/kd, Zic2^m1Nisw/

m1Nisw

Zhang and Niswander (2013), Nagai et al. (2000), Klootwijk et al. (2000), Purandare et al. (2002), Elms et al.

(2003), Inoue et al. (2004), and Furushima et al. (2005) Zic3^Bn/Bn, Zic3^Bn/Y

Zic3^−/−, Zic3^−/Y Zic5^−/−(a), Zic5^−/−(b) Spina bifida (and

curled tail)

Zic2^Ku/+, Zic2^kd/kd, Zic2^m1Nisw/

m1Nisw

(Zhang and Niswander (2013), Garber (1952), Nagai et al. (2000), Klootwijk et al. (2000), and Elms et al. (2003) Zic3^Bn/Bn, Zic3^Bn/Y

Omphalocele Zic3^Bn/Bn, Zic3^Bn/Y Klootwijk et al. (2000) Cleft lip Zic3^Bn/Bn, Zic3^Bn/Y Klootwijk et al. (2000) Cranial neural crest

deficit

Zic2^Ku/Ku, Zic2^kd/kd Nagai et al. (2000), Elms et al. (2003), Inoue et al. (2004), and Furushima et al. (2005)

Zic5^−/−(a), Zic5^−/−(b) Trunk neural crest

deficit

Zic2^Ku/Ku Elms et al. (2003)

Hindbrain patterning Zic2^Ku/Ku Elms et al. (2003) Skeletal defects

Craniofacial Zic5^−/−(a), Zic5^−/−(b) Inoue et al. (2004) and Furushima et al. (2005)

Sternum/ribs Zic5^−/−(a), Zic1^−/− Aruga et al. (1999) and Inoue et al.

(2004)

Vertebral arches Zic1^−/− GrüNeberg (1963), Aruga et al. (1999), Nagai et al. (2000), Purandare et al.

(2002), and Inoue et al. (2004, 2007) Zic2^kd/kd, Zic2^kd/+;Zic3^Bn/Y

Zic3^Bn/X, Zic3^Bn/Bn, Zic3^Bn/Y, Zic3^−/+

Zic3^−/−, Zic3^−/Y Zic5^−/−(a) Tail (reduced number

and or dysmorphic caudal vertebrae)

Zic2^kd/^kd GrüNeberg (1963), Purandare et al.

(2002), Inoue et al. (2004), and Ahmed et al. (2013)

Zic3^Bn/X, Zic3^Bn/Bn, Zic3^Bn/^YZic3^−/+

Zic3^−/−, Zic3^−/Y Zic3^Ka/+

Zic5^−/−(a)

Limb Zic2^kd/kd Nagai et al. (2000)

Classical HPE Zic2^Ku/Ku Warr et al. (2008)

(continued)