Biomedical subjects

Ryuichi Shirasaki

Publications and source records attributed to Ryuichi Shirasaki.

6 recordsLinked to original sources

PubMed2006

FGF as a target-derived chemoattractant for developing motor axons genetically programmed by the LIM code.

LIM transcription factors confer developing axons with specific navigational properties, but the downstream guidance receptors and ligands are not well defined. The dermomyotome, a transient structure from which axial muscles arise, is the source of a secreted long-range chemoattractant specific for medial-class spinal motor neuron axons (MMCm axons). We show that fibroblast growth factors (FGFs) produced by the dermomyotome selectively attract MMCm axons in vitro. FGF receptor 1 (FGFR1) expression is restricted to MMCm neurons, and conditional deletion of FGFR1 causes motor axon guidance defects. Furthermore, reprogramming the identity of limb-innervating motor neurons to that of dermomyotome-innervating MMCm cells using the LIM factor Lhx3 induces FGFR1 expression and shifts an increased number of motor axons to an FGF-responsive state. These results point to a role for FGF signaling in axon guidance and further unravel how downstream effectors of LIM codes direct wiring of the developing nervous system.

Animals↗

PubMed2006

T-Box transcription factor Tbx20 regulates a genetic program for cranial motor neuron cell body migration.

Members of the T-box transcription factor family (Tbx) are associated with several human syndromes during embryogenesis. Nevertheless, their functions within the developing CNS remain poorly characterized. Tbx20 is expressed by migrating branchiomotor/visceromotor (BM/VM) neurons within the hindbrain during neuronal circuit formation. We examined Tbx20 function in BM/VM cells using conditional Tbx20-null mutant mice to delete the gene in neurons. Hindbrain rhombomere patterning and the initial generation of post-mitotic BM/VM neurons were normal in Tbx20 mutants. However, Tbx20 was required for the tangential (caudal) migration of facial neurons, the lateral migration of trigeminal cells and the trans-median movement of vestibuloacoustic neurons. Facial cell soma migration defects were associated with the coordinate downregulation of multiple components of the planar cell polarity pathway including Fzd7, Wnt11, Prickle1, Vang1 and Vang2. Our study suggests that Tbx20 programs a variety of hindbrain motor neurons for migration, independent of directionality, and in facial neurons is a positive regulator of the non-canonical Wnt signaling pathway.

Animals↗

PubMed2005

Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains.

Contact-dependent signaling between membrane-linked ligands and receptors such as the ephrins and Eph receptor tyrosine kinases controls a wide range of developmental and pathological processes. Paradoxically, many cell types coexpress both ligands and receptors, raising the question of how specific signaling readouts are achieved under these conditions. Here, we studied the signaling activities exerted by coexpressed EphA receptors and GPI-linked ephrin-A ligands in spinal motor neuron growth cones. We demonstrate that coexpressed Eph and ephrin proteins segregate laterally into distinct membrane domains from which they signal opposing effects on the growth cone: EphAs direct growth cone collapse/repulsion and ephrin-As signal motor axon growth/attraction. This subcellular arrangement of Eph-ephrin proteins enables axons to discriminate between cis- versus trans-configurations of ligand/receptor proteins, thereby allowing the utilization of both Ephs and ephrins as functional guidance receptors within the same neuronal growth cone.

Animals↗

PubMed2004

Beta1 integrins in muscle, but not in motor neurons, are required for skeletal muscle innervation.

In vitro studies have provided evidence that beta1 integrins in motor neurons promote neurite outgrowth, whereas beta1 integrins in myotubes regulate acetylcholine receptor (AChR) clustering. Surprisingly, using genetic studies in mice, we show here that motor axon outgrowth and neuromuscular junction (NMJ) formation in large part are unaffected when the integrin beta1 gene (Itgb1) is inactivated in motor neurons. In the absence of Itgb1 expression in skeletal muscle, interactions between motor neurons and muscle are defective, preventing normal presynaptic differentiation. Motor neurons fail to terminate their growth at the muscle midline, branch excessively, and develop abnormal nerve terminals. These defects resemble the phenotype of agrin-null mice, suggesting that signaling molecules such as agrin, which coordinate presynaptic and postsynaptic differentiation, are not presented properly to nerve terminals. We conclude that Itgb1 expression in muscle, but not in motor neurons, is critical for NMJ development.

Agrin↗

PubMed2003

Pathfinding and growth termination of primary trigeminal sensory afferents in the embryonic rat hindbrain.

Axons of the trigeminal ganglion convey sensory information from mechanoreceptors, thermoreceptors, and nociceptors in the face and nasal mucosa, then terminate on several groups of neurons including the principal sensory nucleus and the nuclei of the spinal trigeminal tract. To understand guidance mechanisms during the development of trigeminal sensory axons (TA) in the embryonic brain, we first investigated the growth pattern of TA in relation to organization in the hindbrain using flat whole-mount preparation from rat. We found that the primary TA from the trigeminal ganglion entered the brainstem and grew longitudinally within the hindbrain. Whereas descending axons ran just medial to the primary vestibular axons to innervate the spinal nucleus, ascending axons stayed near the entry point. In flat whole-mount culture, the TA extended both ascending and descending branches as they do in vivo. Rostral hindbrain was found to be a less permissive substrate for the TA compared to caudal hindbrain. In addition, the nonpermissive property of the ventral hindbrain substrate restricted the invasion of TA along the entire length of the hindbrain. Thus, cooperation of absolute and relative permissiveness of the substrate plays important roles in the guidance of TA to their targets.

Afferent Pathways↗

PubMed2002

Transcriptional codes and the control of neuronal identity.

The topographic assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Studies of motor neuron development in the spinal cord have begun to elucidate the molecular mechanisms involved in controlling motor projections. In this review, we first describe the actions of transcription factors within motor neuron progenitors, which initiate a cascade of transcriptional interactions that lead to motor neuron specification. We next highlight the contribution of the LIM homeodomain (LIM-HD) transcription factors in establishing motor neuron subtype identity. Importantly, it has recently been shown that the combinatorial expression of LIM-HD transcription factors, the LIM code, confers motor neuron subtypes with the ability to select specific axon pathways to reach their distinct muscle targets. Finally, the downstream targets of the LIM code are discussed, especially in the context of subtype-specific motor axon pathfinding.

Animals↗