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The Beat generation: a multigene family encoding IgSF proteins related to the Beat axon guidance molecule in Drosophila

Howard Hughes Medical Institute, Division of Neurobiology, Department of Molecular and Cell Biology, 519 LSA, University of California, Berkeley, CA 94720, USA

View larger version (106K): [in a new window]   Fig. 1. Alignment of predicted protein sequences of the Beats. CLUSTALW alignment of the best predicted protein sequences for all of the Beats through the Ig domains, generated using a combination of gene predictions from genomic sequence, homology to Beat Ia and cDNA or partial cDNA sequences. Highlighting denotes residues that are identical to Beat Ia. Sequences not shown could not be reliably predicted and are omitted.

View larger version (33K): [in a new window]   Fig. 2. Phylogenetic tree and predicted protein structures of the Beats. (A) Phylogenetic tree constructed from the alignment in Fig. 1, noting cytological locations and clustering. (B) Predicted protein structures of all the Beats for which the entire ORF has been sequenced. Beat Ia is predicted to be a dimerized secreted protein, while the rest are predicted to be membrane anchored, either by transmembrane domains or a GPI link.

View larger version (108K): [in a new window]   Fig. 3. Expression patterns of the Beats. Ventral or ventral oblique views of embryonic mRNA in situ using probes constructed from cDNAs or PCR fragments of the Beats noted. Anterior is towards the left. Arrowheads indicate faint expression.

View larger version (11K): [in a new window]   Fig. 4. Structure of the genomic locus of the class I Beats. Shown are the locations and direction of transcription of the class I Beats at chromosome band 35 on 2L; distal regions are to the left. Each of the genomic loci of the Beats appears to be roughly as large (15-20 kb) and complex as this. Intervening genes are omitted. Chromosomal deficiency stocks used in this study are depicted below. The breakpoints for Df(2L)RA5 and Df(2L)TE35D-GW11 were mapped originally for this study; the breakpoints for the other Dfs listed are from Fambrough and Goodman (Fambrough and Goodman, 1996).

View larger version (141K): [in a new window]   Fig. 5. Restricted expression of beat Ic mRNA is required for normal ISNb development. (A,B) Embryonic mRNA in situ using beat Ia or beat Ic, double-labeled with mAb BP102, which labels all CNS axons. Anterior is towards the left. At stage embryonic 13, beat Ia is expressed strongly in all motoneurons (A), while beat Ic is expressed in a much more restricted subset of neurons (B). In particular, very weak beat Ic expression can be seen in the aCC motoneuron (diagonal arrow) and no beat Ic expression can be detected in the RP motoneurons (vertical arrow). (C) Two abdominal segments of a wild-type stage 16 embryo, stained with anti-FasII mAb 1D4 to visualize motoneurons. At this stage, the axons that compose the ISNb have separated and spread out to innervate their appropriate muscle targets. In particular, the RP3 axon can be seen innervating the cleft between muscles 6 and 7 (arrows). (D) Two abdominal segments from a similarly-prepared elav-GAL4; UAS-beat Ic embryo. Increasing the levels of Beat Ic causes axons to tangle and stall as they enter their target muscle field (large arrow). Motoneuron RP3 is often seen to be delayed in growing into the cleft between muscles 6 and 7 (small arrow).

View larger version (92K): [in a new window]   Fig. 6. Transverse nerve phenotypes in beat Ic mutants. (A) An abdominal segment in a wild-type stage late 16 embryo that shows the TNs growing on the segment boundaries on either side. The TN is fully developed by this stage, and the LBD axon has tightly fasciculated with the TMN axon (large arrow). The TMN axon can sometimes be seen innervating muscle 25 at this stage (small arrow). (B) An abdominal segment in a beat Ic mutant (Df(2L)TE35D-GW19/Df(2L)RM5) embryo at stage late 16, showing TN fasciculation defects (arrows). The TMN axon and the LBD axon are both wandering onto the surface of the ventral muscles instead of fasciculating with each other. (C) Another abdominal segment in a beat Ic mutant embryo. The TMN and LBD axons appear to be growing right past each other (arrow). The TN growing on the adjacent segment boundary is relatively normal.

View larger version (11K): [in a new window]   Fig. 7. Model for Beat Ia-mediated regulation of membrane-anchored Beat adhesion complexes. In this model, a subset of axons expresses a membrane-anchored Beat (white diamonds) that forms heterophilic adhesion complexes with an unknown Beat receptor in trans. Beat Ia (black diamonds) is secreted by a different subset of growth cones at defasciculation choice points and binds to the Beat receptor, displacing the adhesion complexes and locally reducing axonal adhesivity.