The Rac-GAP alpha2-Chimaerin Signals via CRMP2 and Stathmins in the Development of the Ocular Motor System.

A precise sequence of axon guidance events is required for the development of the ocular motor system. Three cranial nerves grow toward, and connect with, six extraocular muscles in a stereotyped pattern, to control eye movements. The signaling protein alpha2-chimaerin (α2-CHN) plays a pivotal role in the formation of the ocular motor system; mutations in CHN1, encoding α2-CHN, cause the human eye movement disorder Duane Retraction Syndrome (DRS). Our research has demonstrated that the manipulation of α2-chn signaling in the zebrafish embryo leads to ocular motor axon wiring defects, although the signaling cascades regulated by α2-chn remain poorly understood. Here, we demonstrate that several cytoskeletal regulatory proteins-collapsin response mediator protein 2 (CRMP2; encoded by the gene dpysl2), stathmin1, and stathmin 2-bind to α2-CHN. dpysl2, stathmin1, and especially stathmin2 are expressed by ocular motor neurons. We find that the manipulation of dpysl2 and of stathmins in zebrafish larvae leads to defects in both the axon wiring of the ocular motor system and the optokinetic reflex, impairing horizontal eye movements. Knockdowns of these molecules in zebrafish larvae of either sex caused axon guidance phenotypes that included defasciculation and ectopic branching; in some cases, these phenotypes were reminiscent of DRS. chn1 knock-down phenotypes were rescued by the overexpression of CRMP2 and STMN1, suggesting that these proteins act in the same signaling pathway. These findings suggest that CRMP2 and stathmins signal downstream of α2-CHN to orchestrate ocular motor axon guidance and to control eye movements.SIGNIFICANCE STATEMENT The precise control of eye movements is crucial for the life of vertebrate animals, including humans. In humans, this control depends on the arrangement of nerve wiring of the ocular motor system, composed of three nerves and six muscles, a system that is conserved across vertebrate phyla. Mutations in the protein alpha2-chimaerin have previously been shown to cause eye movement disorders (squint) and axon wiring defects in humans. Our recent work has unraveled how alpha2-chimaerin coordinates axon guidance of the ocular motor system in animal models. In this article, we demonstrate key roles for the proteins CRMP2 and stathmin 1/2 in the signaling pathway orchestrated by alpha2-chimaerin, potentially giving insight into the etiology of eye movement disorders in humans.

The assembly of developing motor neurons depends on an interplay between spontaneous activity, type II cadherins and gap junctions.

A core structural and functional motif of the vertebrate central nervous system is discrete clusters of neurons or 'nuclei'. Yet the developmental mechanisms underlying this fundamental mode of organisation are largely unknown. We have previously shown that the assembly of motor neurons into nuclei depends on cadherin-mediated adhesion. Here, we demonstrate that the emergence of mature topography among motor nuclei involves a novel interplay between spontaneous activity, cadherin expression and gap junction communication. We report that nuclei display spontaneous calcium transients, and that changes in the activity patterns coincide with the course of nucleogenesis. We also find that these activity patterns are disrupted by manipulating cadherin or gap junction expression. Furthermore, inhibition of activity disrupts nucleogenesis, suggesting that activity feeds back to maintain integrity among motor neurons within a nucleus. Our study suggests that a network of interactions between cadherins, gap junctions and spontaneous activity governs neuron assembly, presaging circuit formation.

C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity.

An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culture model activates programmed cell death and TDP-43 cleavage in a dose-dependent manner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being the most toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a key mediator of cytotoxicity and that cross-talk between DPR proteins likely modifies their pathogenic status in C9ALS/FTD.

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin.

Eye movements depend on correct patterns of connectivity between cranial motor axons and the extraocular muscles. Despite the clinical importance of the ocular motor system, little is known of the molecular mechanisms underlying its development. We have recently shown that mutations in the Chimaerin-1 gene encoding the signaling protein α2-chimaerin (α2-chn) perturb axon guidance in the ocular motor system and lead to the human eye movement disorder, Duane retraction syndrome (DRS). The axon guidance cues that lie upstream of α2-chn are unknown; here we identify candidates to be the Semaphorins (Sema) 3A and 3C, acting via the PlexinA receptors. Sema3A/C are expressed in and around the developing extraocular muscles and cause growth cone collapse of oculomotor neurons in vitro. Furthermore, RNAi knockdown of α2-chn or PlexinAs in oculomotor neurons abrogates Sema3A/C-dependent growth cone collapse. In vivo knockdown of endogenous PlexinAs or α2-chn function results in stereotypical oculomotor axon guidance defects, which are reminiscent of DRS, whereas expression of α2-chn gain-of-function constructs can rescue PlexinA loss of function. These data suggest that α2-chn mediates Sema3-PlexinA repellent signaling. We further show that α2-chn is required for oculomotor neurons to respond to CXCL12 and hepatocyte growth factor (HGF), which are growth promoting and chemoattractant during oculomotor axon guidance. α2-chn is therefore a potential integrator of different types of guidance information to orchestrate ocular motor pathfinding. DRS phenotypes can result from incorrect regulation of this signaling pathway.

A Comparative Study Between an Oil-in-Water Emulsion and Nonlipid Eye Drops Used for Rewetting Contact Lenses.

OBJECTIVES: The purpose of this study was to determine the clinical impact of using SYSTANE BALANCE Lubricant Eye Drops (Alcon, Fort Worth, TX), an oil-in-water emulsion, as a rewetting eye drop in symptomatic contact lens wearers. METHODS: Subjects who had previously experienced contact lens discomfort (CLD), with a mean lens wearing history of 18.6±12.8 years, were randomly assigned to use a Test (SYSTANE BALANCE Lubricant Eye Drops; n=76) or control (habitual nonlipid contact lens rewetting eye drop; n=30) drop over their contact lenses within 5 min of lens insertion and then subsequently at 2 hr intervals up to a maximum of 4 drops per eye daily for a 1-month period. Assessments of subjective comfort, comfortable wearing time, lid wiper epitheliopathy (LWE), and corneal staining were conducted at baseline and after 1 month, after 6 hr of lens wear. RESULTS: Comfort, wearing time, LWE, and corneal staining all showed statistically significant improvements in the test group using SYSTANE BALANCE Lubricant Eye Drops at the 1-month visit compared with baseline data (all P<0.01) and compared with the control group at the 1-month visit (P<0.01, P=0.01, P<0.01, and P=0.03, respectively). CONCLUSIONS: The use of SYSTANE BALANCE Lubricant Eye Drops as a rewetting drop in a group of wearers who experienced symptoms of CLD improved subjective comfort scores, increased comfortable wearing time, and reduced signs of LWE and corneal staining, when compared with the use of non-lipid-containing contact lens rewetting eye drops.

α2-Chimaerin regulates a key axon guidance transition during development of the oculomotor projection.

The ocular motor system consists of three nerves which innervate six muscles to control eye movements. In humans, defective development of this system leads to eye movement disorders, such as Duane Retraction Syndrome, which can result from mutations in the α2-chimaerin signaling molecule. We have used the zebrafish to model the role of α2-chimaerin during development of the ocular motor system. We first mapped ocular motor spatiotemporal development, which occurs between 24 and 72 h postfertilization (hpf), with the oculomotor nerve following an invariant sequence of growth and branching to its muscle targets. We identified 52 hpf as a key axon guidance "transition," when oculomotor axons reach the orbit and select their muscle targets. Live imaging and quantitation showed that, at 52 hpf, axons undergo a switch in behavior, with striking changes in the dynamics of filopodia. We tested the role of α2-chimaerin in this guidance process and found that axons expressing gain-of-function α2-chimaerin isoforms failed to undergo the 52 hpf transition in filopodial dynamics, leading to axon stalling. α2-chimaerin loss of function led to ecotopic and misguided branching and hypoplasia of oculomotor axons; embryos had defective eye movements as measured by the optokinetic reflex. Manipulation of chimaerin signaling in oculomotor neurons in vitro led to changes in microtubule stability. These findings demonstrate that a correct level of α2-chimaerin signaling is required for key oculomotor axon guidance decisions, and provide a zebrafish model for Duane Retraction Syndrome.

Tar DNA-binding protein-43 (TDP-43) regulates axon growth in vitro and in vivo.

Intracellular inclusions of the TAR-DNA binding protein 43 (TDP-43) have been reported in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD-TDP). Rare mutations in TARDBP have been linked to both ALS and FTD-TDP suggesting that TDP-43 dysfunction is mechanistic in causing disease. TDP-43 is a predominantly nuclear protein with roles in regulating RNA transcription, splicing, stability and transport. In ALS, TDP-43 aberrantly accumulates in the cytoplasm of motor neurons where it forms aggregates. However it has until recently been unclear whether the toxic effects of TDP-43 involve recruitment to motor axons, and what effects this might have on axonal growth and integrity. Here we use chick embryonic motor neurons, in vivo and in vitro, to model the acute effects of TDP-43. We show that wild-type and two TDP-43 mutant proteins cause toxicity in chick embryonic motor neurons in vivo. Moreover, TDP-43 is increasingly mislocalised to axons over time in vivo, axon growth to peripheral targets is truncated, and expression of neurofilament-associated antigen is reduced relative to control motor neurons. In primary spinal motor neurons in vitro, a progressive translocation of TDP-43 to the cytoplasm occurs over time, similar to that observed in vivo. This coincides with the appearance of cytoplasmic aggregates, a reduction in the axonal length, and cellular toxicity, which was most striking for neurons expressing TDP-43 mutant forms. These observations suggest that the capacity of spinal motor neurons to produce and maintain an axon is compromised by dysregulation of TDP-43 and that the disruption of cytoskeletal integrity may play a role in the pathogenesis of ALS and FTD-TDP.

Relationships Between Success Factors in Daily Disposable Multifocal Contact Lenses.

Purpose: To explore links between subjective comfort and vision in habitual multifocal soft contact lens (MFCL) wearers when refit with daily disposable MFCLs, to determine which factors are relevant for success with MFCLs and evaluate consistency between MFCLs of different designs. Patients and Methods: This work examined subjective measures in a randomised, participant masked, bilateral wear crossover study at five optometry practices. Fifty-eight habitual MFCL wearers wore stenfilcon A multifocal (stenA-MF; CooperVision Inc) and delefilcon A multifocal (delA-MF; Alcon) for two-weeks. Subjective ratings included satisfaction with comfort and vision and agreement questions. Results: Agreement with "I would like to wear this MFCL in the future" was taken to indicate success with each MFCL; agreement was significantly higher with stenA-MF. There was strong correlation between agreement responses for "I would like to wear this MFCL in the future" and "MFCL met my needs for vision" with both lenses (p<0.01). However, it was only with stenA-MF, which had higher agreement responses to both statements (p<0.05), that responses to these two statements correlated with satisfaction with end-of-day (EOD) comfort (p<0.01). These differences in correlations between the two lenses are seemingly driven by greater satisfaction with stenA-MF for near and intermediate vision (p<0.05). Conclusion: Subjective vision and comfort were only correlated when vision met the needs of most participants. Meeting participants' needs for vision correlated strongly with wanting to wear a MFCL. Results indicate that meeting vision needs is more important than meeting comfort needs when influencing whether presbyopic patients continue wearing MFCLs.

Cadherin-7 and cadherin-6B differentially regulate the growth, branching and guidance of cranial motor axons.

Cadherin-7 (Cad7) and cadherin-6B (Cad6B) are expressed in early and late phases of cranial motoneuron development, respectively. Cad7 is expressed by cranial motoneurons soon after they are generated, as well as in the environment through which their axons extend. By contrast, Cad6B is expressed by mature cranial motoneurons. We demonstrate in chick that these cadherins play distinct roles in cranial motor axon morphology, branching and projection. Using in vitro approaches, we show that Cad7 enhances motor axon outgrowth, suppresses the formation of multiple axons and restricts interstitial branching, thus promoting the development of a single unbranched axon characteristic of differentiating motoneurons. Conversely, Cad6B in vitro promotes motor axon branching, a characteristic of mature motoneurons. In vivo gain- and loss-of-function experiments for these cadherins yielded phenotypes consistent with this interpretation. In particular, a loss of cadherin-mediated interactions in vivo led to dysregulation of the cranial motoneuron normal branching programme and caused axon navigation defects. We also demonstrate that Cad6B functions via the phosphatidylinositol 3-kinase pathway. Together, these data show that Cad7 and Cad6B differentially regulate cranial motoneuron growth, branching and axon guidance.

Facilitating early activities of daily living retraining to prevent functional decline in older adults.

BACKGROUND/AIM: Older people admitted to acute hospitals are at risk of functional decline. There is limited research into strategies that reduce such risks. The aim of this study was to investigate whether individualised activities of daily living retraining programmes improve functional outcomes, influence the choice of discharge destinations and reduce length of stay for older people in acute care. METHODS: A pilot non-randomised controlled study (pre-test/post-test) with block allocation to control and intervention groups was undertaken in an acute geriatric unit at a large teaching hospital. The study was conducted over a six-month period in two consecutive blocks. The intervention group received activities of daily living retraining three times per week for up to one hour per session. The control group received standard, mainly assessment-based occupational therapy services. The Modified Barthel Index was used to measure functional status on admission and discharge. RESULTS: At discharge, there was no statistical difference in the change of total Modified Barthel Index score between control and intervention groups. Of the 10 items scored on the Modified Barthel Index, ambulation and chair/bed transfers approached significance (P = 0.0603 and P = 0.0547 respectively). No evidence was found for a difference in length of stay between intervention and control groups (mean length of stay 15.2 vs. 11.7 days respectively, P = 0.19). Raw data suggested that retraining programmes may reduce the level of care patients required on discharge. CONCLUSIONS: Trends from this study indicate that functional retraining programmes could be effective in preventing functional decline. Further research is needed to reach more definite conclusions.

Evaluating the Performance of Verofilcon A Daily Disposable Contact Lenses in a Group of Heavy Digital Device Users.

Purpose: The purpose of this study was to evaluate the performance of verofilcon A daily disposable contact lenses (CL) in CL wearers who identified themselves as heavy digital device users. Patients and Methods: This prospective, non-masked, open-label study enrolled CL wearers who reported ≥6 hours digital device use per day. Participants were dispensed with the verofilcon A study lenses for 14±2 days, to be worn for at least 5 days a week and 10 hours per day, while continuing their normal routine of digital device use. Participants rated the lens performance at the Day 14 visit using a 0-100 (with 100 being best) scale. Ratings were completed at lens insertion, after 6 hours of digital device use, just before CL removal and for overall experience. Participants also completed a 4-point (strongly agree/disagree, slightly agree/disagree) Likert scale-based questionnaire. Results: Thirty-two participants were eligible and completed the study (27 females; age 25.8 ± 6.0 years, ranging from 19 to 40). Overall lens performance ratings at the Day 14 visit (mean ± standard deviation) for comfort, dryness, and clarity of vision were 91 ± 11, 88 ± 11, and 92 ± 9, respectively. Subjective ratings were stable throughout the day with no significant differences after insertion, after 6 hours of digital device use and before CL removal (all p>0.05). The majority of participants agreed that the study lenses performed well, provided good all-day comfort (28/32; p<0.01) and good all-day vision (29/32; p<0.01). Participants also agreed that after ≥6 hours of digital device use they were satisfied with CL comfort (27/32; p<0.01), vision (29/32; p<0.01) and that the lenses provided good performance (26/32; p<0.01). Conclusion: Verofilcon A lenses were found to perform well, with high ratings for comfort, dryness and vision that remained high throughout the day, during extensive digital device use.

Patterning and axon guidance of cranial motor neurons.

The cranial motor nerves control muscles involved in eye, head and neck movements, feeding, speech and facial expression. The generic and specific properties of cranial motor neurons depend on a matrix of rostrocaudal and dorsoventral patterning information. Repertoires of transcription factors, including Hox genes, confer generic and specific properties on motor neurons, and endow subpopulations at various axial levels with the ability to navigate to their targets. Cranial motor axon projections are guided by diffusible cues and aided by guideposts, such as nerve exit points, glial cells and muscle primordia. The recent identification of genes that are mutated in human cranial dysinnervation disorders is now shedding light on the functional consequences of perturbations of cranial motor neuron development.

Exploring the factors which impact overall satisfaction with single vision contact lenses.

PURPOSE: To explore the impact of subjective factors (lens handling, comfort and vision) on overall single vision contact lens satisfaction. METHODS: Correlation analysis of a prospective, randomised, double-masked, bilateral crossover study involving 55 adapted lens wearers fitted with somofilcon A (SiHy) (clariti® 1 day, CooperVision) and etafilcon A (Hy) (1 DAY ACUVUE® MOIST, Johnson & Johnson Vision) was conducted. Subjective ratings of lens handling, comfort and vision collected after 1 week of lens wear for each lens type were correlated with overall satisfaction. Data were analysed by combining data for both lens types and also for each lens separately. RESULTS: For the combined analysis, significant correlations (p < 0.01) were found between subjective ratings of overall satisfaction and ratings of handing for application (r = 0.64), handling for removal (r = 0.50), comfort upon application (r = 0.59), comfort at end of day (r = 0.61), overall satisfaction with comfort (r = 0.88) and overall satisfaction with vision (r = 0.64). Correlation analysis of the per lens data showed that lens specific correlations of overall satisfaction with handling for lens application varied greatly with lens material (SiHy: r = 0.26, p = 0.05 vs Hy: r = 0.72, p < 0.01). Correlation strength of comfort upon application/at end of day with overall satisfaction also varied with lens material (Application: SiHy: r = 0.40 vs Hy: r = 0.61; End of day: SiHy: r = 0.76 vs Hy: r = 0.58; all p ≤ 0.01). CONCLUSION: Overall satisfaction was significantly correlated with the specific subjective evaluations of handling, vision and comfort. Correlations of overall satisfaction and ease of handling for each lens type suggest that, for habitual contact lens wearers, dissatisfaction with handling at the time of lens application can play a major role in overall dissatisfaction with a lens. Handling for application had a similar correlation (r) value as vision, suggesting that handling for application should not be underestimated when considering overall patient satisfaction.

Working together to improve the care of older people: a new framework for collaboration.

AIM: This paper is a report of a study identifying the care issues experienced by older people in the acute setting that could be improved through a collaborative approach to action. BACKGROUND: Actively involving consumers in the governance of healthcare organizations is viewed positively, although there is less agreement on how to do this. Co-operative inquiry is a useful approach to involve consumers and clinicians in structured dialogue about understanding and changing care, whereas traditional quality improvement methodologies are often singular in their dimensions of change. METHOD: Using a co-operative inquiry approach, five workshops were facilitated over a 4-month period in 2008 with four volunteer older people, four clinicians and three facilitators (n=11). All participants were actively involved in generating ideas and actions using a range of facilitation techniques and data collection methods. FINDINGS: There was increased awareness, understanding and acceptance of clinicians' and consumers' experiences and expectations of care. The complexity behind changing so-called simple care (providing warm drinks, appetizing food), which were the key concerns for consumers, relied on the active management and broader transformation of the system, including teamwork, communication processes and organizational and individual values and beliefs. CONCLUSION: Consumers and clinicians put different emphasis on perspectives related to improving care of older people in the acute hospital setting. The disconnect between what consumers viewed as 'simple' organizational behaviours to change and what the clinicians viewed as complex, led to a recognition that the approach to organizational change needs to be reconceptualized.

Cadherins regulate nuclear topography and function of developing ocular motor circuitry.

In the vertebrate central nervous system, groups of functionally related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.

Global trends in myopia management attitudes and strategies in clinical practice - 2019 Update.

PURPOSE: A survey in 2015 identified a high level of eye care practitioner concern about myopia with a reported moderately high level of activity, but the vast majority still prescribed single vision interventions to young myopes. This research aimed to update these findings 4 years later. METHODS: A self-administrated, internet-based questionnaire was distributed in eight languages, through professional bodies to eye care practitioners globally. The questions examined: awareness of increasing myopia prevalence, perceived efficacy of available strategies and adoption levels of such strategies, and reasons for not adopting specific strategies. RESULTS: Of the 1336 respondents, concern was highest (9.0 ±â€¯1.6; p < 0.001) in Asia and lowest (7.6 ±â€¯2.2; p < 0.001) in Australasia. Practitioners from Asia also considered their clinical practice of myopia control to be the most active (7.7 ±â€¯2.3; p < 0.001), the North American practitioners being the least active (6.3 ±â€¯2.9; p < 0.001). Orthokeratology was perceived to be the most effective method of myopia control, followed by pharmaceutical approaches and approved myopia control soft contact lenses (p < 0.001). Although significant intra-regional differences existed, overall, most practitioners did not consider single-vision distance under-correction to be an effective strategy for attenuating myopia progression (79.6 %), but prescribed single vision spectacles or contact lenses as the primary mode of correction for myopic patients (63.6 ±â€¯21.8 %). The main justifications for their reluctance to prescribe alternatives to single vision refractive corrections were increased cost (20.6 %) and inadequate information (17.6 %). CONCLUSIONS: While practitioner concern about myopia and the reported level of activity have increased over the last 4 years, the vast majority of eye care clinicians still prescribe single vision interventions to young myopes. With recent global consensus evidence-based guidelines having been published, it is hoped that this will inform the practice of myopia management in future.

TDP-43 causes neurotoxicity and cytoskeletal dysfunction in primary cortical neurons.

TDP-43-mediated proteinopathy is a key factor in the pathology of amyotrophic lateral sclerosis (ALS). A potential underlying mechanism is dysregulation of the cytoskeleton. Here we investigate the effects of expressing TDP-43 wild-type and M337V and Q331K mutant isoforms on cytoskeletal integrity and function, using rat cortical neurons in vitro. We find that TDP-43 protein becomes mislocalised in axons over 24-72 hours in culture, with protein aggregation occurring at later timepoints (144 hours). Quantitation of cell viability showed toxicity of both wild-type and mutant constructs which increased over time, especially of the Q331K mutant isoform. Analysis of the effects of TDP-43 on axonal integrity showed that TDP-43-transfected neurons had shorter axons than control cells, and that growth cone sizes were smaller. Axonal transport dynamics were also impaired by transfection with TDP-43 constructs. Taken together these data show that TDP-43 mislocalisation into axons precedes cell death in cortical neurons, and that cytoskeletal structure and function is impaired by expression of either TDP-43 wild-type or mutant constructs in vitro. These data suggest that dysregulation of cytoskeletal and neuronal integrity is an important mechanism for TDP-43-mediated proteinopathy.

Neuronal development: putting motor neurons in their place.

In the developing spinal cord, motor neurons occupy discrete columns with different identities and axon projections. This organisation has now been shown to depend crucially on sequential phases of expression of Hox-c proteins, generated in response to fibroblast growth factor signals.

Axon guidance: mice and men need Rig and Robo.

For many growing axons, navigating across the midline of the nervous system is a crucial stage of their development. New studies on mice and humans show that the axon guidance receptor Robo3/Rig1 is indispensable for axons to accomplish this task.