Reference Report

Reference
Citation	Twombly, V., Bangi, E., Le, V., Malnic, B., Singer, M.A., Wharton, K.A. (2009). Functional analysis of saxophone, the Drosophila gene encoding the BMP type I receptor ortholog of human ALK1/ACVRL1 and ACVR1/ALK2. Genetics 183(2): 563--579. (Export to RIS)
FlyBase ID	FBrf0209213
Publication Type	Research paper
PubMed ID	19620392
PubMed Abstract	In metazoans, bone morphogenetic proteins (BMPs) direct a myriad of developmental and adult homeostatic events through their heterotetrameric type I and type II receptor complexes. We examined 3 existing and 12 newly generated mutations in the Drosophila type I receptor gene, saxophone (sax), the ortholog of the human Activin Receptor-Like Kinase1 and -2 (ALK1/ACVRL1 and ALK2/ACVR1) genes. Our genetic analyses identified two distinct classes of sax alleles. The first class consists of homozygous viable gain-of-function (GOF) alleles that exhibit (1) synthetic lethality in combination with mutations in BMP pathway components, and (2) significant maternal effect lethality that can be rescued by an increased dosage of the BMP encoding gene, dpp+. In contrast, the second class consists of alleles that are recessive lethal and do not exhibit lethality in combination with mutations in other BMP pathway components. The alleles in this second class are clearly loss-of-function (LOF) with both complete and partial loss-of-function mutations represented. We find that one allele in the second class of recessive lethals exhibits dominant-negative behavior, albeit distinct from the GOF activity of the first class of viable alleles. On the basis of the fact that the first class of viable alleles can be reverted to lethality and on our ability to independently generate recessive lethal sax mutations, our analysis demonstrates that sax is an essential gene. Consistent with this conclusion, we find that a normal sax transcript is produced by saxP, a viable allele previously reported to be null, and that this allele can be reverted to lethality. Interestingly, we determine that two mutations in the first class of sax alleles show the same amino acid substitutions as mutations in the human receptors ALK1/ACVRl-1 and ACVR1/ALK2, responsible for cases of hereditary hemorrhagic telangiectasia type 2 (HHT2) and fibrodysplasia ossificans progressiva (FOP), respectively. Finally, the data presented here identify different functional requirements for the Sax receptor, support the proposal that Sax participates in a heteromeric receptor complex, and provide a mechanistic framework for future investigations into disease states that arise from defects in BMP/TGF-beta signaling.
DOI	10.1534/genetics.109.105585
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Secondary IDs
Language of Publication	English
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Publication Type	Journal
Abbreviation	Genetics
Title	Genetics
Publication Year	1916-
ISBN/ISSN	0016-6731
Data from Reference
Aberrations (11)
	Df(2L)JS17 Df(2R)H23 Df(2R)P32a Df(2R)sax^1rv2 Df(2R)sax^PE7 Df(2R)sax-H9 Df(2R)sax-H30 Df(2R)ST1 Dp(2;1)sax^1rv2 Dp(2;2)B16 Dp(2;2)DTD48
Alleles (24)
	dpp^d5 dpp^d12 dpp^d-ho dpp^e87 dpp^hr4 dpp^hr27 dpp^hr56 dpp^hr90 dpp^Sal20 Mad¹² sax¹ sax^1rv1 sax^1rv5 sax² sax³ sax⁴ sax⁵ sax⁶ sax^hs.PB sax^P sax^PE5 sax^PE10 scw^E1 scw^E2
Constructs (2)
	P{dpp-Sal20} P{hs-sax}
Genes (10)
	brk dpp gbb Kr Mad N sax scw Su(H) tkv
Insertions (3)
	H{Lw2}J21.31 H{Lw2}SW283 P{lacW}sax^P
Natural transposons (1)
	hobo