RALDH-independent generation of retinoic acid during vertebrate embryogenesis by CYP1B1
2007
Several independent lines of evidence have revealed an instructive role for
retinoic acid (RA) signalling in the establishment of normal pattern and
cellular specification of the vertebrate embryo. Molecular analyses have
previously identified the major RA-synthesising (RALDH1-3) and RA-degrading
(CYP26A-C1) enzymes as well as other components involved in RA processing
(e.g. CRABP). Although the majority of the early effects of RA can be
attributed to the activity of RALDH2, many other effects are suggestive of the
presence of an as yet unidentified RA source. Here we describe the
identification, expression, biochemistry and functional analysis of CYP1B1, a
member of the cytochrome p450 family of mono-oxygenases, and provide evidence
that it contributes to RA synthesis during embryonic patterning. We present in
vitro biochemical data demonstrating that this enzyme can generate both
all- trans -retinal ( t -RAL) and all- trans -retinoic
acid ( t -RA) from the precursor all- trans -retinol
( t -ROH), but unlike the CYP26s, CYP1B1 cannot degrade t -RA.
In particular, we focussed on the capacity of CYP1B1 to regulate the molecular
mechanisms associated with dorsoventral patterning of the neural tube and
acquisition of motor neuron progenitor domain identity. Concordant with its
sites of expression and biochemistry, data are presented demonstrating that
CYP1B1 is capable of eliciting responses that are consistent with the
production of RA. Taken together, we propose that these data provide strong
support for CYP1B1 being one of the RALDH-independent components by which
embryos direct RA-mediated patterning.
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