PMID- 10631181
OWN - NLM
STAT- MEDLINE
DCOM- 20000309
LR  - 20220215
IS  - 0950-1991 (Print)
IS  - 0950-1991 (Linking)
VI  - 127
IP  - 3
DP  - 2000 Feb
TI  - Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal
      mouse limb and the genetics of distal limb diversity.
PG  - 605-19
AB  - In this study, we use a mouse insertional mutant to delineate gene activities
      that shape the distal limb skeleton. A recessive mutation that results in
      brachydactyly was found in a lineage of transgenic mice. Sequences flanking the
      transgene insertion site were cloned, mapped to chromosome 3, and used to
      identify the brachydactyly gene as the type IB bone morphogenetic protein
      receptor, BmprIB (ALK6). Expression analyses in wild-type mice revealed two major
      classes of BmprIB transcripts. Rather than representing unique coding RNAs
      generated by alternative splicing of a single pro-mRNA transcribed from one
      promoter, the distinct isoforms reflect evolution of two BmprIB promoters: one
      located distally, driving expression in the developing limb skeleton, and one
      situated proximally, initiating transcription in neural epithelium. The distal
      promoter is deleted in the insertional mutant, resulting in a regulatory allele
      (BmprIB(Tg)) lacking cis-sequences necessary for limb BmprIB expression. Mutants 
      fail to generate digit cartilage, indicating that BMPRIB is the physiologic
      transducer for the formation of digit cartilage from the skeletal blastema.
      Expansion of BmprIB expression into the limb through acquisition of these distal 
      cis-regulatory sequences appears, therefore, to be an important genetic component
      driving morphological diversity in distal extremities. GDF5 is a BMP-related
      signal, which is also required for proper digit formation. Analyses incorporating
      both Gdf5 and BmprIB(Tg) alleles revealed that BMPRIB regulates chondrogenesis
      and segmentation through both GDF5-dependent and -independent processes, and
      that, reciprocally, GDF5 acts through both IB and other type I receptors.
      Together, these findings provide in vivo support for the concept of combinatorial
      BMP signaling, in which distinct outcomes result both from a single receptor
      being triggered by different ligands and from a single ligand binding to
      different receptors.
FAU - Baur, S T
AU  - Baur ST
AD  - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
FAU - Mai, J J
AU  - Mai JJ
FAU - Dymecki, S M
AU  - Dymecki SM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Development
JT  - Development (Cambridge, England)
JID - 8701744
RN  - 0 (Bone Morphogenetic Proteins)
RN  - 0 (Gdf5 protein, mouse)
RN  - 0 (Growth Differentiation Factor 5)
RN  - 0 (Growth Substances)
RN  - 0 (Receptors, Growth Factor)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.30 (Bmpr1b protein, mouse)
RN  - EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type I)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Body Patterning
MH  - Bone Morphogenetic Protein Receptors, Type I
MH  - *Bone Morphogenetic Proteins
MH  - Bone and Bones/embryology
MH  - Cartilage, Articular/*embryology
MH  - *Chromosome Mapping
MH  - Extremities/embryology
MH  - *Gene Expression Regulation, Developmental
MH  - Genotype
MH  - Growth Differentiation Factor 5
MH  - Growth Substances/*genetics/physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Osteogenesis/*genetics
MH  - Promoter Regions, Genetic
MH  - Protein Serine-Threonine Kinases/*genetics/physiology
MH  - Receptors, Growth Factor/*genetics/physiology
MH  - Toes/abnormalities
MH  - Transcription, Genetic
EDAT- 2000/01/13 09:00
MHDA- 2000/03/11 09:00
CRDT- 2000/01/13 09:00
PHST- 2000/01/13 09:00 [pubmed]
PHST- 2000/03/11 09:00 [medline]
PHST- 2000/01/13 09:00 [entrez]
AID - 10.1242/dev.127.3.605 [doi]
PST - ppublish
SO  - Development. 2000 Feb;127(3):605-19. doi: 10.1242/dev.127.3.605.