Academic journal article Genetics

Tissue Architecture in the Caenorhabditis Elegans Gonad Depends on Interactions among Fibulin-1, Type IV Collagen and the ADAMTS Extracellular Protease

Academic journal article Genetics

Tissue Architecture in the Caenorhabditis Elegans Gonad Depends on Interactions among Fibulin-1, Type IV Collagen and the ADAMTS Extracellular Protease

Article excerpt

ABSTRACT Molecules in the extracellular matrix (ECM) regulate cellular behavior in both development and pathology. Fibulin-1 is a conserved ECM protein. The Caenorhabditis elegans ortholog, FBL-1, regulates gonad-arm elongation and expansion by acting antagonistically to GON-1, an ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family protease. The elongation of gonad arms is directed by gonadal distal tip cells (DTCs). Here we report that a dominant mutation in the EMB-9/type IV collagen a1 subunit can compensate for loss of FBL-1 activity in gonadogenesis. A specific amino acid substitution in the noncollagenous 1 (NC1) domain of EMB-9 suppressed the fbl-1 null mutant. FBL-1 was required to maintain wild-type EMB-9 in the basement membrane (BM), whereas mutant EMB-9 was retained in the absence of FBL-1. EMB-9 (either wild type or mutant) localization in the BM enhanced PAT-3/β-integrin expression in DTCs. In addition, overexpression of PAT-3 partially rescued the DTC migration defects in fbl-1 mutants, suggesting that EMB-9 acts in part through PAT-3 to control DTC migration. In contrast to the suppression of fbl-1(tk45), mutant EMB-9 enhanced the gonadal defects of gon-1(e1254), suggesting that it gained a function similar to that of wild-type FBL-1, which promotes DTC migration by inhibiting GON-1. We propose that FBL-1 and GON-1 control EMB-9 accumulation in the BM and promote PAT-3 expression to control DTC migration.

COLLECTIVE cell migration is among the major strategies to shape tissues and organs (Bianco et al. 2007; Ewald et al. 2008; Lu and Werb 2008; Montell 2008; Friedl and Gilmour 2009; Rorth 2009). In this process, remodeling of the extracellular matrix (ECM) positively and negatively affects the interactions between basement membranes (BMs) and migrating cells or epithelia to yield the proper cell geometry and tissue architecture. However, how the ECM is remodeled and how migrating cells interact with changing ECM milieus during organogenesis is mostly unknown.

The development of Caenorhabditis elegans hermaphrodite gonads is regulated by migration of the gonadal leader cells, distal tip cells (DTCs), which promote the directional elongation of the gonad arms during the larval stages to form the U-shaped gonads found in adult animals (Kimble and Hirsh 1979; Hedgecock et al. 1987). Two secreted ADAMTS family metalloproteases, GON-1 and MIG-17, act cooperatively in this process; GON-1 is required for the motility of DTCs and gonadal expansion, whereas MIG-17 acts to control the direction of DTC movement but does not control DTC motility per se (Blelloch and Kimble 1999; Nishiwaki et al. 2000). GON-1 expressed in DTCs and that expressed in body wall muscles regulate gonadal elongation and expansion, respectively (Blelloch and Kimble 1999). GON-1 and MIG-17 are proposed to remodel the BM proteolytically to regulate the microenvironment that affects gonad shaping (Blelloch et al. 1999; Blelloch and Kimble 1999; Nishiwaki et al. 2000). GON-1 and FBL-1, a fibulin-1 ortholog in C. elegans, act antagonistically during gonadogenesis (Hesselson et al. 2004). GON-1 is homologous to mammalian ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) proteinases ADAMTS-9 and ADAMTS-20 (Llamazares et al. 2003; Somerville et al. 2003). ADAMTS-5, ADAMTS-9, and ADAMTS-20 cooperate with fibulin-1 to promote regression of the interdigital web by generating active versican fragments in the mouse (McCulloch et al. 2009).

To uncover new components involved in the antagonistic interaction between FBL-1 and GON-1 to control gonadogenesis, we conducted a suppressor analysis of fbl-1(tk45) null mutants. Two independently isolated suppressors were found to be identical mutations in the gene emb-9, which was previously identified by embryonic lethal mutations and encodes the type IV collagen a1 chain (Miwa et al. 1980; Guo et al. 1991). In contrast to the suppression of fbl-1, the emb-9 mutation enhanced the gonadal defects of gon-1. …

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