Abstract
LIM-homeodomain (HD) transcription factors form a multimeric complex and assign neuronal subtype identities, as demonstrated by the hexameric ISL1-LHX3 complex which gives rise to somatic motor (SM) neurons. However, the roles of combinatorial LIM code in motor neuron diversification and their subsequent differentiation is much less well understood. In the present study, we demonstrate that the ISL1 controls postmitotic cranial branchiomotor (BM) neurons including the positioning of the cell bodies and peripheral axon pathfinding. Unlike SM neurons, which transform into interneurons, BM neurons are normal in number and in marker expression in Isl1 mutant mice. Nevertheless, the movement of trigeminal and facial BM somata is stalled, and their peripheral axons are fewer or misrouted, with ectopic branches. Among genes whose expression level changes in previous ChIP-seq and microarray analyses in Isl1-deficient cell lines, we found that Slit2 transcript was almost absent from BM neurons of Isl1 mutants. Both ISL1-LHX3 and ISL1-LHX4 bound to the Slit2 enhancer and drove endogenous Slit2 expression in SM and BM neurons. Our findings suggest that combinations of ISL1 and LHX factors establish cell-type specificity and functional diversity in terms of motor neuron identities and/or axon development.
Highlights
Motor neurons (MNs) transmit signals from the CNS to peripheral muscles to control voluntary and involuntary movements
In wild-type E11.5 hindbrain flat-mount tissues and transverse sections, ISL1 is present in all cranial motor neurons including the facial branchiomotor (FBM) neurons, which migrate from r4 to r6 (Fig. 1A,E)
We demonstrated that BM/visceral motor (VM) neurons did arise in Isl[1] mutants but their BM neurons were defective to varying degrees in cell body migration and axon projection, supporting their combinatorial action
Summary
Motor neurons (MNs) transmit signals from the CNS to peripheral muscles to control voluntary and involuntary movements. ISLET1 (ISL1) is a member of the LIM-HD transcription factor family present in all MNs. Its role in acquisition of motor neuron identity in the spinal cord is well-established[6,7,8,9,10]. Unlike other LIM-HD family members, ISL1 appears to act together with other LHX factors in the CNS such as spinal cord motor neurons and striatal interneurons[2,19]. It is uncertain whether a similar combinatorial LIM-code is employed in most neurons in general. We suggest that Slit[2] is a downstream target of ISL1 in cranial motor neurons and ISL1 controls axon pathfinding in cranial motor neurons
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