Rieger syndrome revisited: experimental approaches using pharmacologic and antisense strategies to abrogate EGF and TGF-alpha functions resulting in dysmorphogenesis during embryonic mouse craniofacial morphogenesis.

The major manifestations of Rieger syndrome (RS), an autosomal dominant disorder, include absent maxillary incisor teeth, malformations of the anterior chamber of the eye, and umbilical anomalies [Aarskog et al., 1983: Am J Med Genet 15:29-38; Gorlin et al., 1990: "Syndromes of the Head and Neck" 3rd ed.]. Linkage of RS to human chromosome 4q markers has been identified with tight linkage to epidermal growth factor (EGF) [Murray et al., 1992: Nat Genet 2:46-48]. Mutations associated with genes of the EGF superfamily are implicated in malformations arising from abnormal development of the first branchial arch [Ardinger et al., 1989: Am J Hum Genet 45:348-353; Sassani et al., 1993: Am J Med Genet 45:565-569]. Down-regulation of EGF during early mouse development results in ablation of tooth formation [Kronmiller et al., 1991: Dev Biol 147:485-488]. Since EGF, TGF-alpha, and EGF receptor (EGFr) transcripts are expressed in the mouse first branchial arch and derivatives, experimental strategies were employed to investigate the consequences of down-regulation of EGF translation and inhibition of EGF receptor during embryonic mandibular morphogenesis. Antisense inhibition of EGF expression produces mandibular dysmorphogenesis with decreased tooth bud size; these effects are reversed by the addition of exogenous EGF to the culture medium [Shum et al., 1993: Development 118:903-917]. Tyrphostin RG 50864, which inhibits EGF receptor kinase activity, inhibits EGF or TGF-alpha stimulation of tyrosine phosphorylation in a concentration-dependent manner and severely retards mandibular development [Shum et al., 1993: Development 118:903-917].(ABSTRACT TRUNCATED AT 250 WORDS)