INTRODUCTION Development of the lacrimal gland is an example of an epithelial-mesenchymal interaction. In the mouse, a single bud- like invagination of the conjunctival epithelium at the temporal extremity of the eye is the initial sign of lacrimal gland

Development of the lacrimal gland is an example of an epithelial-mesenchymal interaction. In the mouse, a single budlike invagination of the conjunctival epithelium at the temporal extremity of the eye is the initial sign of lacrimal gland formation (Kammandel et al., 1999). The mesenchymal cells that surround the point of epithelial budding are the periocular cells, of neural crest origin (Johnston et al., 1979). The tubular invagination of the lacrimal gland extends and branches multiple times to give the lobular structure of the mature gland (Kammandel et al., 1999). The type of morphogenesis (Hogan, 1999) that accompanies development of the lacrimal gland has been studied in detail in several other organ systems, including the limb (Martin, 1998), the lung (Peters et al., 1994; Hogan and Yingling, 1998; Weaver et al., 1999) and teeth (Peters and Balling, 1999). As a result of these analyses, a selection of soluble signaling molecules has been implicated in generating morphology of this type. These include sonic hedgehog (Bellusci et al., 1997a; Pepicelli et al., 1998) and members of the bone morphogenetic protein (BMP) (Graff, 1997) and fibroblast growth factor (FGF) families (Mason et al., 1994). In particular, FGF10, also known as keratinocyte growth factor-2 (KGF2), has been implicated in budding outgrowth of epithelia (Bellusci et al., 1997b; Ohuchi et al., 1997; Sekine et al., 1999). Both FGF7 and FGF10 can bind to and signal through fibroblast growth factor receptor-2 (FGFR2 (Ornitz et al., 1996)). The mouse FGFR2 gene has alternative splicing for exons 8 and 9 and this results in an alternative amino-acid sequence in the C-terminal half of the third immunoglobulin fold of the extracellular domain. The IIIb (exon 8) isoform is known as the KGF receptor and the IIIc isoform as bek (Johnson and Williams, 1993; Xu et al., 1998). bek binds with high affinity to FGF1, FGF2, FGF4 and FGF5 but not FGF7 (Ornitz et al., 1996). In contrast, the KGFR binds FGF7 and FGF10 as well as FGF1; the binding of FGF2 to the KGFR is at very low affinity (Miki et al., 1992; Lu et al., 1999). The observation that expression of the KGFR is restricted to epithelial lineages and that bek is found only in mesenchymal cells (Orr-Urtreger et al., 1993b; Iseki et al., 1997; Xu et al., 1998) indicates that tissue-specific alternative splicing is one way to provide FGF signaling specificity. The Pax6 gene is expressed in many tissues of the eye 2563 Development 127, 2563-2572 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV4343