Pigment epithelium-derived factor (PEDF) , a neurotrophic agent first identified in conditioned medium from cultured human retinal pigment epithelial cells, induces neuronal differentiation. DNA sequence analysis shows PEDF belongs to the serine protease inhibitor(SERPIN) gene family, but PEDF does not seem to exhibit antiprotease activity. PEDF have "gliastatic" effect, along with neuron-survival character. PEDF appeared to inhibit angiogenesis by causing apoptosis of activated endothelial cells. The concentration of PEDF in the cornea and vitreous is sufficient to inhibit angiogenic stimulatory activity. PEDF is taken as one of the most effective antiangiogenic factors. It may prove to be a useful therapeutic for neuronal damage and inhibiting angiogenesis may be particularly effective.

Pigment epithelium derived factor:a potent inhibitor of angiogenesis

Metazoan cytoplasmic dynein moves processively along microtubules with the aid of dynactin and an adaptor protein that joins dynein and dynactin into a stable ternary complex. Here, we examined how Hook3, a cargo adaptor involved in Golgi and endosome transport, forms a motile dynein-dynactin complex. We show that the conserved Hook domain interacts directly with the dynein light intermediate chain 1 (LIC1). By solving the crystal structure of the Hook domain and using structure-based mutagenesis, we identify two conserved surface residues that are each critical for LIC1 binding. Hook proteins with mutations in these residues fail to form a stable dynein-dynactin complex, revealing a crucial role for LIC1 in this interaction. We also identify a region of Hook3 specifically required for an allosteric activation of processive motility. Our work reveals the structural details of Hook3's interaction with dynein and offers insight into how cargo adaptors form processive dynein-dynactin motor complexes.

/pdf/assembly-and-activation-of-dynein-dynactin-by-the-cargo-29j4bt5mdc.pdf

Assembly and activation of dynein-dynactin by the cargo adaptor protein Hook3.

Sperm differentiation requires specific protein transport for correct sperm tail formation and head shaping. A transient microtubular structure, the manchette, appears around the differentiating spermatid head and serves as a platform for protein transport to the growing tail. Sperm flagellar 2 (SPEF2) is known to be essential for sperm tail development. In this study we investigated the function of SPEF2 during spermatogenesis using a male germ cell-specific Spef2 knockout mouse model. In addition to defects in sperm tail development, we observed a duplication of the basal body and failure in manchette migration resulting in an abnormal head shape. We identified cytoplasmic dynein 1 and GOLGA3 as novel interaction partners for SPEF2. SPEF2 and dynein 1 colocalize in the manchette and the inhibition of dynein 1 disrupts the localization of SPEF2 to the manchette. Furthermore, the transport of a known SPEF2-binding protein, IFT20, from the Golgi complex to the manchette was delayed in the absence of SPEF2. These data indicate a possible novel role of SPEF2 as a linker protein for dynein 1-mediated cargo transport along microtubules.

/pdf/spef2-functions-in-microtubule-mediated-transport-in-w986ii8wdv.pdf

SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation.

Purpose.
To investigate neuroprotective and axogenic properties of pigment epithelium-derived factor (PEDF) in retinal ganglion cells (RGC) in vitro and in vivo.

Pigment Epithelium-Derived Factor Is Retinal Ganglion Cell Neuroprotective and Axogenic After Optic Nerve Crush Injury

All animal cells use the motor cytoplasmic dynein 1 (dynein) to transport diverse cargo toward microtubule minus ends and to organize and position microtubule arrays such as the mitotic spindle. Cargo-specific adaptors engage with dynein to recruit and activate the motor, but the molecular mechanisms remain incompletely understood. Here, we use structural and dynamic nuclear magnetic resonance (NMR) analysis to demonstrate that the C-terminal region of human dynein light intermediate chain 1 (LIC1) is intrinsically disordered and contains two short conserved segments with helical propensity. NMR titration experiments reveal that the first helical segment (helix 1) constitutes the main interaction site for the adaptors Spindly (SPDL1), bicaudal D homolog 2 (BICD2), and Hook homolog 3 (HOOK3). In vitro binding assays show that helix 1, but not helix 2, is essential in both LIC1 and LIC2 for binding to SPDL1, BICD2, HOOK3, RAB-interacting lysosomal protein (RILP), RAB11 family-interacting protein 3 (RAB11FIP3), ninein (NIN), and trafficking kinesin-binding protein 1 (TRAK1). Helix 1 is sufficient to bind RILP, whereas other adaptors require additional segments preceding helix 1 for efficient binding. Point mutations in the C-terminal helix 1 of Caenorhabditis elegans LIC, introduced by genome editing, severely affect development, locomotion, and life span of the animal and disrupt the distribution and transport kinetics of membrane cargo in axons of mechanosensory neurons, identical to what is observed when the entire LIC C-terminal region is deleted. Deletion of the C-terminal helix 2 delays dynein-dependent spindle positioning in the one-cell embryo but overall does not significantly perturb dynein function. We conclude that helix 1 in the intrinsically disordered region of LIC provides a conserved link between dynein and structurally diverse cargo adaptor families that is critical for dynein function in vivo.

/pdf/a-transient-helix-in-the-disordered-region-of-dynein-light-1ntr7lrx1j.pdf

A transient helix in the disordered region of dynein light intermediate chain links the motor to structurally diverse adaptors for cargo transport.

Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells However, in mammals, few mutants are available for studying the effects of defects in dynein-controlled processes in the context of the whole organism Here, we deleted mouse Dlic1 gene encoding DLIC1, a subunit of the dynein complex Dlic1−/− mice are viable, but display severe photoreceptor degeneration Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins, and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rab11-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER), but seems not to affect vesicle transport from the ER to Golgi Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors, probably due to the impaired transport function of dynein Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS, and is required for photoreceptor development and survival The Dlic1−/− mice also provide a new mouse model to study human retinal degeneration

/pdf/dlic1-deficiency-impairs-ciliogenesis-of-photoreceptors-by-23m9sa6trs.pdf

Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein.

Microphthalmia-associated transcription factor acts through PEDF to regulate RPE cell migration

Correction to: Cell Research (2013) 23:835-850. doi:10.1038/cr.2013.59; published online 30 April 2013 The authors apologized for the mis-spelling of the second author's name and the delay notice. The correct form is as follows. Shanshan Kong, Xingrong Du, Chao Peng, Yiming Wu, Huirong Li, Xi Jin, Ling Hou, Kejing Deng, Tian Xu, Wufan Tao

/pdf/erratum-dlic1-deficiency-impairs-ciliogenesis-of-5cp8zxkfdq.pdf

Erratum: Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

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Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein.

Microphthalmia-associated transcription factor acts through PEDF to regulate RPE cell migration

Erratum: Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein