Search

Liprins are a multifunctional family of scaffold proteins, identified by their involvement in several important neuronal functions related to signaling and organization of synaptic structures. More recently, the knowledge on the liprin family has expanded from neuronal functions to processes relevant to cancer progression, including cell adhesion, cell motility, cancer cell invasion, and signaling. These proteins consist of regions, which by prediction are intrinsically disordered, and may be involved in the assembly of supramolecular structures relevant for their functions. This review summarizes the current understanding of the functions of liprins in different cellular processes, with special emphasis on liprins in tumor progression. The available data indicate that liprins may be potential biomarkers for cancer progression and may have therapeutic importance.

Networks of scaffold proteins and enzymes assemble at the interface between the cytosol and specific sites of the plasma membrane, where these networks guide distinct cellular functions. Some of these plasma membrane–associated platforms (PMAPs) include shared core components that are able to establish specific protein–protein interactions, to produce distinct supramolecular assemblies regulating dynamic processes as diverse as cell adhesion and motility, or the formation and function of neuronal synapses. How cells organize such dynamic networks is still an open question. In this review we introduce molecular networks assembling at the edge of migrating cells, and at pre– and postsynaptic sites, which share molecular players that can drive the assembly of biomolecular condensates. Very recent experimental evidence has highlighted the emerging role of some of these multidomain/scaffold proteins belonging to the GIT, liprin-α and ELKS/ERC families as drivers of liquid–liquid phase separation (LLPS). The data point to an important role of LLPS: (i) in the formation of PMAPs at the edge of migrating cells, where LLPS appears to be involved in promoting protrusion and the turnover of integrin–mediated adhesions, to allow forward cell translocation; (ii) in the assembly of the presynaptic active zone and of the postsynaptic density deputed to the release and reception of neurotransmitter signals, respectively. The recent results indicate that LLPS at cytosol–membrane interfaces is suitable not only for the regulation of active cellular processes, but also for the continuous spatial rearrangements of the molecular interactions involved in these dynamic processes.

Small Rho GTPases such as Cdc42 and Rac1 regulate peripheral myelination during development. Deletion of Rac1 in Schwann cell conditional knockout mice causes a delay in the process of radial sorting, followed by hypomyelination as well as defective PAK1 activation and high number of immature Oct6+ Schwann cells. Rac3 has been shown to have redundant, specific and even opposite functions to Rac1 depending on the cell type, age and other factors. In neuronal cells, evidence suggests that Rac3 may oppose Rac1 by disrupting PAK1-GIT1-Paxillin signaling thus preventing cell differentiation and extension of lamellipodia. Therefore, we tested if these Rho GTPases have similar or opposite functions in Schwann cells, by deleting the genes for both proteins in mice during peripheral myelination. At P30, global deletion of Rac3 alleviates the developmental defects on axonal sorting and hypomyelination that are caused by Schwann cell conditional ablation of Rac1. Moreover, Rac3 deletion also reverses the arrest of Schwann cells at the Oct6+ stage and ameliorates the defects in PAK1 phosphorylation observed in Rac1 deficient mice. This partial rescue of the phenotype declines later on with aging. Since double transgenic animals showed dysmyelination without axonal degeneration at P60, we postulate that this deterioration is not likely due to loss of Rac3 in neurons, but it seems to be a Schwann cell-specific defect in the maintenance of myelin.

Liquid–liquid phase separation drives the formation of biomolecular condensates (BCs) for the spatiotemporal organization of several cellular processes. Recent evidences indicate that components of plasma-membrane-associated platforms form biomolecular condensates near focal adhesions (FAs), and suggest that phase separation regulates dynamic processes occurring at the front of migrating cells.

Charcot-Marie-Tooth type 4B1 (CMT4B1) is a severe autosomal recessive demyelinating neuropathy with childhood onset, caused by loss-of-function mutations in the myotubularin-related 2 (MTMR2) gene. MTMR2 is a ubiquitously expressed catalytically active 3-phosphatase, which in vitro dephosphorylates the 3-phosphoinositides PtdIns3P and PtdIns(3,5)P(2), with a preference for PtdIns(3,5)P(2). A hallmark of CMT4B1 neuropathy are redundant loops of myelin in the nerve termed myelin outfoldings, which can be considered the consequence of altered growth of myelinated fibers during postnatal development. How MTMR2 loss and the resulting imbalance of 3′-phosphoinositides cause CMT4B1 is unknown. Here we show that MTMR2 by regulating PtdIns(3,5)P(2) levels coordinates mTORC1-dependent myelin synthesis and RhoA/myosin II-dependent cytoskeletal dynamics to promote myelin membrane expansion and longitudinal myelin growth. Consistent with this, pharmacological inhibition of PtdIns(3,5)P(2) synthesis or mTORC1/RhoA signaling ameliorates CMT4B1 phenotypes. Our data reveal a crucial role for MTMR2-regulated lipid turnover to titrate mTORC1 and RhoA signaling thereby controlling myelin growth.

We present the discoveries of KELT-25b (TIC 65412605, TOI-626.01) and KELT-26b (TIC 160708862, TOI-1337.01), two transiting companions orbiting relatively bright, early A-stars. The transit signals were initially detected by the KELT survey, and subsequently confirmed by \textit{TESS} photometry. KELT-25b is on a 4.40-day orbit around the V = 9.66 star CD-24 5016 ($T_{\rm eff} = 8280^{+440}_{-180}$ K, $M_{\star}$ = $2.18^{+0.12}_{-0.11}$ $M_{\odot}$), while KELT-26b is on a 3.34-day orbit around the V = 9.95 star HD 134004 ($T_{\rm eff}$ =$8640^{+500}_{-240}$ K, $M_{\star}$ = $1.93^{+0.14}_{-0.16}$ $M_{\odot}$), which is likely an Am star. We have confirmed the sub-stellar nature of both companions through detailed characterization of each system using ground-based and \textit{TESS} photometry, radial velocity measurements, Doppler Tomography, and high-resolution imaging. For KELT-25, we determine a companion radius of $R_{\rm P}$ = $1.64^{+0.039}_{-0.043}$ $R_{\rm J}$, and a 3-sigma upper limit on the companion's mass of $\sim64~M_{\rm J}$. For KELT-26b, we infer a planetary mass and radius of $M_{\rm P}$ = $1.41^{+0.43}_{-0.51}$ $M_{\rm J}$ and $R_{\rm P}$ = $1.940^{+0.060}_{-0.058}$ $R_{\rm J}$. From Doppler Tomographic observations, we find KELT-26b to reside in a highly misaligned orbit. This conclusion is weakly corroborated by a subtle asymmetry in the transit light curve from the \textit{TESS} data. KELT-25b appears to be in a well-aligned, prograde orbit, and the system is likely a member of a cluster or moving group., 24 pages, 18 figures, 8 tables

Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of Rac1 and Rac3 (Atoh1-Cre;Rac1(flox/flox);Rac3(-/-)) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of Atoh1-Cre; Rac1(flox/flox);Rac3(-/-) mice at P8. Atoh1-Cre;Rac1(flox/flox);Rac3(-/-) CGNs differentiated normally until expression of p27(kip1) and NeuN in the deep EGL at P5. Primary CGNs and cerebellar microexplants from Atoh1-Cre;Rac1(flox/flox);Rac3(-/-) mice exhibited impaired neuritogenesis, which was more apparent in Map2-positive dendrites. Such findings suggest that impaired tangential migration and final differentiation of CGNs have resulted in decreased cerebellum size and agenesis of the medial internal granule layer, respectively. Furthermore, Rac depleted/deleted cells exhibited decreased levels of Mid1 and impaired mTORC1 signaling. Mid1 depletion in CGNs produced mild impairments in neuritogenesis and reductions in mTORC1 signaling. Thus, a novel Rac-signaling pathway (Rac1Mid1-mTORC1) may be involved in medial cerebellar development.

The Rac1 and Rac3 GTPases are co-expressed in the developing nervous system, where they are involved in different aspects of neuronal development, including the formation of synapses. The deletion of both Rac genes determines a stronger reduction of dendritic spines in vitro compared to the knockout of either gene, indicating that Rac1 and Rac3 play a synergistic role in the formation of these structures. Here, we have addressed the role of each GTPase in the formation of dendritic spines by overexpressing either Rac1 or Rac3 in wildtype neurons, or by re-expressing either GTPase in double knockout hippocampal cultures. We show that the Rac3 protein is expressed with Rac1 in developing hippocampal neurons. Overexpression of either GTPase in WT neurons increases the density of dendritic spines, suggesting the involvement of both GTPases in their formation. We also found that the re-expression of either Rac1 or Rac3 in double knockout neurons is sufficient to restore spinogenesis. Rac1 is significantly more efficient than Rac3 in restoring the formation of spines. On the other hand the quantitative analysis in neurons overexpressing or re-expressing either GTPase shows that Rac3 induces a more pronounced increase in the size of the spines compared to Rac1. These enlarged spines form morphological synapses identified by the juxtaposition of postsynaptic and presynaptic markers. Thus, while Rac1 appears more efficient in inducing the formation of mature spines, Rac3 is more efficient in promoting their enlargement. Our study highlights specific roles of Rac1 and Rac3, which may be functionally relevant also to synaptic plasticity.

We present the discovery of KELT-22Ab, a hot Jupiter from the KELT-South survey. KELT-22Ab transits the moderately bright (V∼11.1) Sun-like G2V star TYC 7518-468-1. The planet has an orbital period of P = 1.3866529±0.0000027 days, a radius of R_P = 1.285^(+0.12)_(−0.071) R_J, and a relatively large mass of M_P = 3.47^(+0.15)_(−0.14) M_J. The star has R⋆ = 1.099^(+0.079)_(−0.046) R⊙, M⋆ = 1.092^(+0.045)_(−0.041) M⊙, T_(eff) = 5767^(+50)_(−49) K, log g⋆ = 4.393^(+0.039)_(−0.060) (cgs), and [m/H] = +0.259^(+0.085)_(−0.083), and thus, other than its slightly super-solar metallicity, appears to be a near solar twin. Surprisingly, KELT-22A exhibits kinematics and a Galactic orbit that are somewhat atypical for thin disk stars. Nevertheless, the star is rotating quite rapidly for its estimated age, shows evidence of chromospheric activity, and is somewhat metal rich. Imaging reveals a slightly fainter companion to KELT-22A that is likely bound, with a projected separation of 6” (∼1400 AU). In addition to the orbital motion caused by the transiting planet, we detect a possible linear trend in the radial velocity of KELT-22A suggesting the presence of another relatively nearby body that is perhaps non-stellar. KELT-22Ab is highly irradiated (as a consequence of the small semi-major axis of a/R⋆ = 4.97), and is mildly inflated. At such small separations, tidal forces become significant. The configuration of this system is optimal for measuring the rate of tidal dissipation within the host star. Our models predict that, due to tidal forces, the semi-major axis of KELT-22Ab is decreasing rapidly, and is thus predicted to spiral into the star within the next Gyr.

Several cellular processes depend on networks of proteins assembled at specific sites near the plasma membrane. Scaffold proteins assemble these networks by recruiting relevant molecules. The scaffold protein ERC1/ELKS and its partners promote cell migration and invasion, and assemble into dynamic networks at the protruding edge of cells. Here by electron microscopy and single molecule analysis we identify ERC1 as an extended flexible dimer. We found that ERC1 scaffolds form cytoplasmic condensates with a behavior that is consistent with liquid phases that are modulated by a predicted disordered region of ERC1. These condensates specifically host partners of a network relevant to cell motility, including liprin-α1, which was unnecessary for the formation of condensates, but influenced their dynamic behavior. Phase separation at specific sites of the cell periphery may represent an elegant mechanism to control the assembly and turnover of dynamic scaffolds needed for the spatial localization and processing of molecules.

Background InformationThe expression of the scaffold protein liprin-1 is upregulated in human breast cancer. This protein is part of a molecular network that is important for tumour cell invasion in vitro. Liprin-1 promotes invasion by supporting the protrusive activity at the leading edge of the migrating tumour cell and the degradation of the extracellular matrix by invadopodia. In this study, we have addressed the role of liprin-1 in the invasive process in vivo and of liprin-proteins in tumor cell motility.ResultsThe human tumour cell line MDA-MB-231 expresses liprin-1 and is able to promote the formation of metastasis in mice. Liprin- proteins may hetero-oligomerize with the members of the subfamily of the liprin- adaptor proteins. Analysis of the role of liprin-1 and liprin-2 has shown that while liprin-1 contributes positively to tumour cell motility in vitro; liprin-2 has a negative effect on both cell motility and invasion. Interestingly, we also observed differential effects on the ability of tumour cells to degrade the extracellular matrix, which is required for efficient invasion by tumour cells. In addition, analysis of the formation of lung metastases in vivo revealed that while the overexpression of liprin-1 in MDA-MB-231 cells did not evidently affect the metastatic process, silencing of the endogenous protein strongly impaired the formation of metastases by two independent invasion assays, without inhibiting the growth of primary tumours.ConclusionsOur data support an important role of distinct liprin family members in the regulation of tumour cell invasion, highlighting pro-invasive and anti-invasive effects by liprin-1 and liprin-2, respectively.SignificanceOur results indicate the importance of liprins in breast cancer cell invasion, and are expected to lead to future investigations on the mechanisms underlying the effects of distinct liprin proteins in different processes linked to tumor cell migration and invasion.

Proxima Centauri has become the subject of intense study since the radial-velocity discovery by Anglada-Escud\'e et al. 2016 of a planet orbiting this nearby M-dwarf every ~ 11.2 days. If Proxima Centauri b transits its host star, independent confirmation of its existence is possible, and its mass and radius can be measured in units of the stellar host mass and radius. To date, there have been three independent claims of possible transit-like event detections in light curve observations obtained by the MOST satellite (in 2014-15), the BSST telescope in Antarctica (in 2016), and the Las Campanas Observatory (in 2016). The claimed possible detections are tentative, due in part to the variability intrinsic to the host star, and in the case of the ground-based observations, also due to the limited duration of the light curve observations. Here, we present preliminary results from an extensive photometric monitoring campaign of Proxima Centauri, using telescopes around the globe and spanning from 2006 to 2017, comprising a total of 329 observations. Considering our data that coincide directly and/or phased with the previously published tentative transit detections, we are unable to independently verify those claims. We do, however, verify the previously reported ubiquitous and complex variability of the host star. We discuss possible interpretations of the data in light of the previous claims, and we discuss future analyses of these data that could more definitively verify or refute the presence of transits associated with the radial-velocity discovered planet., Comment: Published in The Astronomical Journal, Volume 155, Number 6. 15 pages, 13 figures, and 2 tables. Updated Table 2 FOVs

The Kilodegree Extremely Little Telescope (KELT) project has been conducting a photometric survey for transiting planets orbiting bright stars for over ten years. The KELT images have a pixel scale of ~23"/pixel---very similar to that of NASA's Transiting Exoplanet Survey Satellite (TESS)---as well as a large point spread function, and the KELT reduction pipeline uses a weighted photometric aperture with radius 3'. At this angular scale, multiple stars are typically blended in the photometric apertures. In order to identify false positives and confirm transiting exoplanets, we have assembled a follow-up network (KELT-FUN) to conduct imaging with higher spatial resolution, cadence, and photometric precision than the KELT telescopes, as well as spectroscopic observations of the candidate host stars. The KELT-FUN team has followed-up over 1,600 planet candidates since 2011, resulting in more than 20 planet discoveries. Excluding ~450 false alarms of non-astrophysical origin (i.e., instrumental noise or systematics), we present an all-sky catalog of the 1,128 bright stars (6, Comment: Accepted for publication in AJ, 21 pages, 12 figures, 7 tables

We present the discovery of KELT-21b, a hot Jupiter transiting the $V=10.5$ A8V star HD 332124. The planet has an orbital period of $P=3.6127647\pm0.0000033$ days and a radius of $1.586_{-0.040}^{+0.039}$ $R_J$. We set an upper limit on the planetary mass of $M_P, Comment: Accepted for publication in AJ. Updated to match accepted version. 25 pages, 14 figures

We report the joint WASP/KELT discovery of WASP-167b/KELT-13b, a transiting hot Jupiter with a 2.02-d orbit around a $V$ = 10.5, F1V star with [Fe/H] = 0.1 $\pm$ 0.1. The 1.5 R$_{\rm Jup}$ planet was confirmed by Doppler tomography of the stellar line profiles during transit. We place a limit of $, Comment: 11 pages, 8 figures, accepted by MNRAS

The amount of ultraviolet irradiation and ablation experienced by a planet depends strongly on the temperature of its host star. Of the thousands of extra-solar planets now known, only four giant planets have been found that transit hot, A-type stars (temperatures of 7300-10,000K), and none are known to transit even hotter B-type stars. WASP-33 is an A-type star with a temperature of ~7430K, which hosts the hottest known transiting planet; the planet is itself as hot as a red dwarf star of type M. The planet displays a large heat differential between its day-side and night-side, and is highly inflated, traits that have been linked to high insolation. However, even at the temperature of WASP-33b's day-side, its atmosphere likely resembles the molecule-dominated atmospheres of other planets, and at the level of ultraviolet irradiation it experiences, its atmosphere is unlikely to be significantly ablated over the lifetime of its star. Here we report observations of the bright star HD 195689, which reveal a close-in (orbital period ~1.48 days) transiting giant planet, KELT-9b. At ~10,170K, the host star is at the dividing line between stars of type A and B, and we measure the KELT-9b's day-side temperature to be ~4600K. This is as hot as stars of stellar type K4. The molecules in K stars are entirely dissociated, and thus the primary sources of opacity in the day-side atmosphere of KELT-9b are likely atomic metals. Furthermore, KELT-9b receives ~700 times more extreme ultraviolet radiation (wavelengths shorter than 91.2 nanometers) than WASP-33b, leading to a predicted range of mass-loss rates that could leave the planet largely stripped of its envelope during the main-sequence lifetime of the host star., 39 pages, 3 figures, 1 table, 3 extended data figures, 3 extended data tables. Published in Nature on 22 June 2017

We report the discovery of KELT-18b, a transiting hot Jupiter in a 2.87d orbit around the bright (V=10.1), hot, F4V star BD+60 1538 (TYC 3865-1173-1). We present follow-up photometry, spectroscopy, and adaptive optics imaging that allow a detailed characterization of the system. Our preferred model fits yield a host stellar temperature of 6670+/-120 K and a mass of 1.524+/-0.069 Msun, situating it as one of only a handful of known transiting planets with hosts that are as hot, massive, and bright. The planet has a mass of 1.18+/-0.11 Mjup, a radius of 1.57+/-0.04 Rjup, and a density of 0.377+/-0.040 g/cm^3, making it one of the most inflated planets known around a hot star. We argue that KELT-18b's high temperature and low surface gravity, which yield an estimated ~600 km atmospheric scale height, combined with its hot, bright host make it an excellent candidate for observations aimed at atmospheric characterization. We also present evidence for a bound stellar companion at a projected separation of ~1100 AU, and speculate that it may have contributed to the strong misalignment we suspect between KELT-18's spin axis and its planet's orbital axis. The inferior conjunction time is 2457542.524998 +/-0.000416 (BJD_TDB) and the orbital period is 2.8717510 +/- 0.0000029 days. We encourage Rossiter-McLaughlin measurements in the near future to confirm the suspected spin-orbit misalignment of this system., 16 pages, 13 figures, 6 tables, accepted to AJ

We present the discovery of the giant planet KELT-19Ab, which transits the moderately bright $(\mathrm{V} \sim 9.9)$ A8V star TYC 764-1494-1 with an orbital period of 4.61 days. We confirm the planetary nature of the companion via a combination of radial velocities, which limit the mass to $< 4.1\,\mathrm{M_J}$ $(3\sigma)$, and a clear Doppler tomography signal, which indicates a retrograde projected spin-orbit misalignment of $\lambda = -179.7^{+3.7}_{-3.8}$ degrees. Global modeling indicates that the $\rm{T_{eff}} =7500 \pm 110\,\mathrm{K}$ host star has $\mathrm{M_*} = 1.62^{+0.25}_{-0.20}\,\mathrm{M_\odot}$ and $\mathrm{R_*} = 1.83 \pm 0.10\,\mathrm{R_\odot}$. The planet has a radius of $\mathrm{R_P}=1.91 \pm 0.11\,\mathrm{R_J}$ and receives a stellar insolation flux of $\sim 3.2\times 10^{9}\,\mathrm{erg\,s^{-1}\,cm^{-2}}$, leading to an inferred equilibrium temperature of $\rm{T_{EQ}} = \sim 1935\,\rm{K}$ assuming zero albedo and complete heat redistribution. With a $v\sin{I_*}=84.8\pm 2.0\,\mathrm{km\,s^{-1}}$, the host is relatively slowly rotating compared to other stars with similar effective temperatures, and it appears to be enhanced in metallic elements but deficient in calcium, suggesting that it is likely an Am star. KELT-19A would be the first detection of an Am host of a transiting planet of which we are aware. Adaptive optics observations of the system reveal the existence of a companion with late G9V/early K1V spectral type at a projected separation of $\approx 160\,\mathrm{AU}$. Radial velocity measurements indicate that this companion is bound. Most Am stars are known to have stellar companions, which are often invoked to explain the relatively slow rotation of the primary. In this case, the stellar companion is unlikely to have caused the tidal braking of the primary. However, it may have emplaced the transiting planetary companion via the Kozai-Lidov mechanism., Comment: Published in The Astronomical Journal. 18 pages, 14 figures, 6 tables

In multiple sclerosis (MS), inflammation leads to damage of central nervous system myelin and axons. Previous studies have postulated impaired GABA transmission in MS, and recent postmortem analysis has shown that GABAergic parvalbumin (PV)-positive interneurons are decreased in the primary motor cortex (M1) of patients with MS. In this report, we present evidence for the loss of a specific population of GABAergic interneurons in the experimental autoimmune encephalomyelitis mouse model of MS. Using experimental autoimmune encephalomyelitis, we evaluated the distribution of both PV-positive interneurons and of the inhibitory presynaptic input in the M1 of experimental autoimmune encephalomyelitis and control mice. Our results demonstrate a specific decrease in the number of PV-positive interneurons in the M1 of mice with experimental autoimmune encephalomyelitis. We detected a significant reduction in the number of PV-positive interneurons in the layers II and III of the M1 of diseased mice, while there was no difference in the number of calretinin (CR)-positive cells between animals with experimental autoimmune encephalomyelitis and control animals. Moreover, we observed a significant reduction in the inhibitory presynaptic input in the M1 of treated mice. These changes were specific for the mice with elevated clinical score, while they were not detectable in the mice with low clinical score. Our results support the hypothesis that reinforcing the action of the GABAergic network may represent a therapeutic alternative to limit the progression of the neuronal damage in MS patients.

Cortical interneurons are characterized by extraordinary functional and morphological diversity. Although tremendous progress has been made in uncovering molecular and cellular mechanisms implicated in interneuron generation and function, several questions still remain open. Rho-GTPases have been implicated as intracellular mediators of numerous developmental processes such as cytoskeleton organization, vesicle trafficking, transcription, cell cycle progression, and apoptosis. Specifically in cortical interneurons, we have recently shown a cell-autonomous and stage-specific requirement for Rac1 activity within proliferating interneuron precursors. Conditional ablation of Rac1 in the medial ganglionic eminence leads to a 50% reduction of GABAergic interneurons in the postnatal cortex. Here we examine the additional role of Rac3 by analyzing Rac1/Rac3 double-mutant mice. We show that in the absence of both Rac proteins, the embryonic migration of medial ganglionic eminence-derived interneurons is further impaired. Postnatally, double-mutant mice display a dramatic loss of cortical interneurons. In addition, Rac1/Rac3-deficient interneurons show gross cytoskeletal defects in vitro, with the length of their leading processes significantly reduced and a clear multipolar morphology. We propose that in the absence of Rac1/Rac3, cortical interneurons fail to migrate tangentially towards the pallium due to defects in actin and microtubule cytoskeletal dynamics.

International audience; Interneurons are essential modulators of brain activity and their abnormal maturation may lead to neural and intellectual disabilities. Here we show that cultures derived from murine medial ganglionic eminences (MGEs) produce virtually pure, polarized γ-aminobutyric acid (GABA)-ergic interneurons that can form morphologically identifiable inhibitory synapses. We show that Rac GTPases and a protein complex including the GIT family scaffold proteins are expressed during maturation in vitro, and are required for the normal development of neurites. GIT1 promotes neurite extension in a conformation-dependent manner, while affecting its interaction with specific partners reduces neurite branching. Proteins of the GIT network are concentrated at growth cones, and interaction mutants may affect growth cone behavior. Our findings identify the PIX/GIT1/liprin-α1/ERC1 network as critical for the regulation of interneuron neurite differentiation in vitro, and show that these cultures represent a valuable system to identify the molecular mechanisms driving the maturation of cortical/hippocampal interneurons.

We intended to compile the most complete catalog of bona fide members and candidate members of the beta Pictoris association, and to measure their rotation periods and basic properties from our own observations, public archives, and exploring the literature. We carried out a multi-observatories campaign to get our own photometric time series and collected all archived public photometric data time series for the stars in our catalog. Each time series was analyzed with the Lomb-Scargle and CLEAN periodograms to search for the stellar rotation periods. We complemented the measured rotational properties with detailed information on multiplicity, membership, and projected rotational velocity available in the literature and discussed star by star. We measured the rotation periods of 112 out of 117 among bona fide members and candidate members of the beta Pictoris association and, whenever possible, we also measured the luminosity, radius, and inclination of the stellar rotation axis. This represents to date the largest catalog of rotation periods of any young loose stellar association. We provided an extensive catalog of rotation periods together with other relevant basic properties useful to explore a number of open issues, such as the causes of spread of rotation periods among coeval stars, evolution of angular momentum, and lithium-rotation connection., Forthcoming article, Received: 20 June 2016 / Accepted: 09 September 2016; 40 pages, 2 figures. The online figures A1-A73 are available at CDS

We announce the discovery of KELT-23Ab, a hot Jupiter transiting the relatively bright ($V=10.3$) star BD+66 911 (TYC 4187-996-1), and characterize the system using follow-up photometry and spectroscopy. A global fit to the system yields host-star properties of $T_{eff}=5900\pm49 K$, $M_*=0.945^{+0.060}_{-0.054} M_{\odot}$, $R_*=0.995\pm0.015 R_{\odot}$, $L_*=1.082^{+0.051}_{-0.048} L_{\odot}$, log$g_{*}=4.418^{+0.026}_{-0.025}$ (cgs), and $\left[{\rm Fe}/{\rm H}\right]=-0.105\pm0.077$. KELT-23Ab is a hot Jupiter with mass $M_P=0.938^{+0.045}_{-0.042} M_{\rm J}$, radius $R_P=1.322\pm0.025 R_{\rm J}$, and density $\rho_P=0.504^{+0.038}_{-0.035}$ g cm$^{-3}$. Intense insolation flux from the star has likely caused KELT-23Ab to become inflated. The time of inferior conjunction is $T_0=2458149.40776\pm0.00091~\rm {BJD_{TDB}}$ and the orbital period is $P=2.255353^{+0.000031}_{-0.000030}$ days. There is strong evidence that KELT-23A is a member of a long-period binary star system with a less luminous companion, and due to tidal interactions, the planet is likely to spiral into its host within roughly a Gyr. This system has one of the highest positive ecliptic latitudes of all transiting planet hosts known to date, placing it near the Transiting Planet Survey Satellite and James Webb Space Telescope continuous viewing zones. Thus we expect it to be an excellent candidate for long-term monitoring and follow-up with these facilities., Comment: 17 pages, 10 figures, Accepted for publication in AJ

We report the discovery of a transiting exoplanet, KELT-11b, orbiting the bright ($V=8.0$) subgiant HD 93396. A global analysis of the system shows that the host star is an evolved subgiant star with $T_{\rm eff} = 5370\pm51$ K, $M_{*} = 1.438_{-0.052}^{+0.061} M_{\odot}$, $R_{*} = 2.72_{-0.17}^{+0.21} R_{\odot}$, log $g_*= 3.727_{-0.046}^{+0.040}$, and [Fe/H]$ = 0.180\pm0.075$. The planet is a low-mass gas giant in a $P = 4.736529\pm0.00006$ day orbit, with $M_{P} = 0.195\pm0.018 M_J$, $R_{P}= 1.37_{-0.12}^{+0.15} R_J$, $\rho_{P} = 0.093_{-0.024}^{+0.028}$ g cm$^{-3}$, surface gravity log ${g_{P}} = 2.407_{-0.086}^{+0.080}$, and equilibrium temperature $T_{eq} = 1712_{-46}^{+51}$ K. KELT-11 is the brightest known transiting exoplanet host in the southern hemisphere by more than a magnitude, and is the 6th brightest transit host to date. The planet is one of the most inflated planets known, with an exceptionally large atmospheric scale height (2763 km), and an associated size of the expected atmospheric transmission signal of 5.6%. These attributes make the KELT-11 system a valuable target for follow-up and atmospheric characterization, and it promises to become one of the benchmark systems for the study of inflated exoplanets., Comment: 15 pages, Submitted to AAS Journals

Liprin-α1 and ERC1 are interacting scaffold proteins regulating the motility of normal and tumor cells. They act as part of plasma membrane-associated platforms at the edge of motile cells to promote protrusion by largely unknown mechanisms. Here we identify an amino-terminal region of the liprin-α1 protein (liprin-N) that is sufficient and necessary for the interaction with other liprin-α1 molecules. Similar to liprin-α1 or ERC1 silencing, expression of the liprin-N negatively affects tumor cell motility and extracellular matrix invasion, acting as a dominant negative by interacting with endogenous liprin-α1 and causing the displacement of the endogenous ERC1 protein from the cell edge. Interfering with the localization of ERC1 at the cell edge inhibits the disassembly of focal adhesions, impairing protrusion. Liprin-α1 and ERC1 proteins colocalize with active integrin β1 clusters distinct from those colocalizing with cytoplasmic focal adhesion proteins and influence the localization of peripheral Rab7-positive endosomes. We propose that liprin-α1 and ERC1 promote protrusion by displacing cytoplasmic adhesion components to favour active integrin internalization into Rab7-positive endosomes.

We present the discovery of a hot-Jupiter transiting the V=9.23 mag main-sequence A-star KELT-17 (BD+14 1881). KELT-17b is a 1.31 -0.29/+0.28 Mj, 1.525 -0.060/+0.065 Rj hot-Jupiter in a 3.08 day period orbit misaligned at -115.9 +/- 4.1 deg to the rotation axis of the star. The planet is confirmed via both the detection of the radial velocity orbit, and the Doppler tomographic detection of the shadow of the planet over two transits. The nature of the spin-orbit misaligned transit geometry allows us to place a constraint on the level of differential rotation in the host star; we find that KELT-17 is consistent with both rigid-body rotation and solar differential rotation rates (alpha < 0.30 at 2 sigma significance). KELT-17 is only the fourth A-star with a confirmed transiting planet, and with a mass of 1.635 -0.061/+0.066 Msun, effective temperature of 7454 +/- 49 K, and projected rotational velocity v sin I_* = 44.2 -1.3/+1.5 km/s; it is amongst the most massive, hottest, and most rapidly rotating of known planet hosts., 15 pages, 9 figures, accepted for publication in AJ

The nervous system influences organ development by direct innervation and the action of hormones. We recently showed that the specific absence of Rac1 in neurons (Rac1(N)) in a Rac3-deficient (Rac3(KO)) background causes motor behavioural defects, epilepsy, and premature mouse death around postnatal day 13. We report here that Rac1(N)/Rac3(KO) mice display a progressive loss of immune-competence. Comparative longitudinal analysis of lymphoid organs from control, single Rac1(N) or Rac3(KO), and double Rac1(N)/Rac3(KO) mutant animals showed that thymus development is preserved up to postnatal day 9 in all animals, but is impaired in Rac1(N)/Rac3(KO) mice at later times. This is evidenced by a drastic reduction in thymic cell numbers. Cell numbers were also reduced in the spleen, leading to splenic tissue disarray. Organ involution occurs in spite of unaltered thymocyte and lymphocyte subset composition, and proper mature T-cell responses to polyclonal stimuli in vitro. Suboptimal thymus innervation by tau-positive neuronal terminals possibly explains the suboptimal thymic output and arrested thymic development, which is accompanied by higher apoptotic rates. Our results support a role for neuronal Rac1 and Rac3 in dictating proper lymphoid organ development, and suggest the existence of lymphoid-extrinsic mechanisms linking neural defects to the loss of immune-competence. "The nervous system influences organ development by direct innervation and the action of hormones. We recently showed that the specific absence of Rac1 in neurons (Rac1(N) ) in a Rac3-deficient (Rac3(KO) ) background causes motor behavioural defects, epilepsy, and premature mouse death around postnatal day 13. We report here that Rac1(N) \/Rac3(KO) mice display a progressive loss of immune-competence. Comparative longitudinal analysis of lymphoid organs from control, single Rac1(N) or Rac3(KO) , and double Rac1(N) \/Rac3(KO) mutant animals showed that thymus development is preserved up to postnatal day 9 in all animals, but is impaired in Rac1(N) \/Rac3(KO) mice at later times. This is evidenced by a drastic reduction in thymic cell numbers. Cell numbers were also reduced in the spleen, leading to splenic tissue disarray. Organ involution occurs in spite of unaltered thymocyte and lymphocyte subset composition, and proper mature T-cell responses to polyclonal stimuli in vitro. Suboptimal thymus innervation by tau-positive neuronal terminals possibly explains the suboptimal thymic output and arrested thymic development, which is accompanied by higher apoptotic rates. Our results support a role for neuronal Rac1 and Rac3 in dictating proper lymphoid organ development, and suggest the existence of lymphoid-extrinsic mechanisms linking neural defects to the loss of immune-competence"

Background information. Cell motility entails the reorganization of the cytoskeleton and membrane trafficking for effective protrusion. The GIT–PIX protein complexes are involved in the regulation of cell motility and adhesion and in the endocytic traffic of members of the family of G-protein-coupled receptors. We have investigated the function of the endogenous GIT complexes in the regulation of cell motility stimulated by fMLP (formyl-Met-Leu-Phe) peptide, in a rat basophilic leukaemia RBL-2H3 cell line stably expressing an HA (haemagglutinin)-tagged receptor for the fMLP peptide. Results. Our analysis shows that RBL cells stably transfected with the chemoattractant receptor expressed both GIT1–PIX and GIT2–PIX endogenous complexes. We have used silencing of the different members of the complex by small interfering RNAs to study the effects on a number of events linked to agonist-induced cell migration. We found that cell adhesion was not affected by depletion of any of the proteins of the GIT complex, whereas agonist-enhanced cell spreading was inhibited. Analysis of agonist-stimulated haptotactic cell migration indicated a specific positive effect of GIT1 depletion on trans-well migration. The internalization of the formyl-peptide receptor was also inhibited by depletion of GIT1 and GIT2. The effects of the GIT complexes on trafficking of the receptors was confirmed by an antibody-enhanced agonist-induced internalization assay, showing that depletion of PIX, GIT1 or GIT2 protein caused decreased perinuclear accumulation of internalized receptors. Conclusions. Our results show that endogenous GIT complexes are involved in the regulation of chemoattractant-induced cell motility and receptor trafficking, and support previous findings indicating an important function of the GIT complexes in the regulation of different G-protein-coupled receptors. Our results also indicate that endogenous GIT1 and GIT2 regulate distinct subsets of agonist-induced responses and suggest a possible functional link between the control of receptor trafficking and the regulation of cell motility by GIT proteins.

Integrins mediate the interaction between cells and extracellular matrix by assembling adhesive structures that need to be dynamically modulated to allow cell motility. We have recently identified liprin-alpha1 as an essential regulator of integrin dynamics required for efficient cell motility. Here we investigated the effects of liprin-alpha1 expression on beta1 integrin receptors. We found that increased levels of liprin-alpha1 affected the localization of inactive, low-affinity integrins, while increasing the average size of beta1 integrin-positive focal adhesions. Although a direct interaction between beta1 integrins and liprin-alpha1 could not be revealed biochemically, a striking colocalization between redistributed inactive beta1 integrins and liprin-alpha1 was observed. The tight association of overexpressed and endogenous liprin-alpha1 to the cytoplasmic side of the ventral plasma membrane suggested a possible role of liprin in stabilizing integrin receptors at the cell surface. In support of this hypothesis, we demonstrated an inhibitory effect of liprin overexpression on antibody-induced beta1 integrin internalization. On the other hand, depletion of endogenous liprin-alpha by small interfering RNA increased the rate of integrin internalization. Overall, these results support the hypothesis that liprin-alpha1 exerts its action on focal adhesion turnover by influencing the localization and stability of integrin receptors at the cell surface.

Integrin activation is needed to link the extracellular matrix with the actin cytoskeleton during cell motility. Protrusion requires coordination of actin dynamics with focal-adhesion turnover. We report that the adaptor protein liprin-alpha1 is stably associated with the cell membrane. Lipin-alpha1 shows a localization that is distinct from that of activated beta1 integrins at the edge of spreading cells. Depletion of liprin-alpha1 inhibits the spreading of COS7 cells on fibronectin by affecting lamellipodia formation, whereas its overexpression enhances spreading, and lamellipodia and focal-adhesion formation at the cell edge. Cooperation between liprin-alpha1 and talin is needed, because either talin or liprin depletion prevents spreading in the presence of the other protein. The effects of liprin on spreading, but not its effects in the reorganization of the cell edge, are dependent on its interaction with leukocyte common antigen-related tyrosine phosphatase receptors. Therefore, liprin is an essential regulator of cell motility that contributes to the effectiveness of cell-edge protrusion.

Rho family GTPases have been implicated as important regulators of neuronal development. Rac3 is a member of this family specifically expressed in vertebrate developing neurons, where it is coexpressed with the ubiquitous Rac1 GTPase. We have previously shown that Rac3 knockout mice are viable and fertile. The Rac3 protein shows highest expression around postnatal day 7 in brain regions relevant for cognitive behaviors. In this study we find that Rac3 knockout mice do not show defects in spatial reference memory assessed with water maze task, but they show a reduced behavioral flexibility to novel situations. Analysis of explorative behavior revealed hyperactive behavior and hyperreactivity to the presentation of new stimuli, as assessed by dark/light box, emergence and novel object tests. These defects were not due to reduced visual abilities, since visual acuity and contrast sensitivity were comparable in Rac3 knockout and wildtype littermates. Our data reinforce the notion that Rho family GTPases are important for normal cognitive development, and highlight specific functions of Rac3 that cannot be compensated by the coexpressed homologous Rac1.

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.

The expression of the scaffold protein liprin-α1 is upregulated in human breast cancer. This protein is part of a molecular network that is important for tumour cell invasion in vitro. Liprin-α1 promotes invasion by supporting the protrusive activity at the leading edge of the migrating tumour cell and the degradation of the extracellular matrix by invadopodia. In this study, we have addressed the role of liprin-α1 in the invasive process in vivo and of liprin-proteins in tumor cell motility.The human tumour cell line MDA-MB-231 expresses liprin-α1 and is able to promote the formation of metastasis in mice. Liprin-α proteins may hetero-oligomerize with the members of the subfamily of the liprin-β adaptor proteins. Analysis of the role of liprin-β1 and liprin-β2 has shown that while liprin-β1 contributes positively to tumour cell motility in vitro; liprin-β2 has a negative effect on both cell motility and invasion. Interestingly, we also observed differential effects on the ability of tumour cells to degrade the extracellular matrix, which is required for efficient invasion by tumour cells. In addition, analysis of the formation of lung metastases in vivo revealed that while the overexpression of liprin-α1 in MDA-MB-231 cells did not evidently affect the metastatic process, silencing of the endogenous protein strongly impaired the formation of metastases by two independent invasion assays, without inhibiting the growth of primary tumours.Our data support an important role of distinct liprin family members in the regulation of tumour cell invasion, highlighting pro-invasive and anti-invasive effects by liprin-α1 and liprin-β2, respectively.Our results indicate the importance of liprins in breast cancer cell invasion, and are expected to lead to future investigations on the mechanisms underlying the effects of distinct liprin proteins in different processes linked to tumor cell migration and invasion.