Tzu-Jen Kao

Taipei Medical University | TMU

Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (prim...

Allopregnanolone (allo) is a physiological regulator of neuronal activity that treats multiple neurological disorders. Allo penetrates the blood–brain barrier with very high efficiency, implying that allo can treat CNS-related diseases, including glioblastoma (GBM), which always recurs after standard therapy. Hence, this study aimed to determine wh...

The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly co...

The complexity of breast cancer includes many interacting biological processes, and proteasome alpha (PSMA) subunits are reported to be involved in many cancerous diseases, although the transcriptomic expression of this gene family in breast cancer still needs to be more thoroughly investigated. Consequently, we used a holistic bioinformatics appro...

During the neural circuit formation, neuronal growth cones must be guided precisely to their neuronal or muscle targets, which can be achieved by the activation of membrane-bound guidance receptors at the periphery. However, the mechanisms that regulate the temporal availability of these receptors remain largely unknown. TAR DNA binding protein-43...

Colorectal cancer (CRC) is one of the world’s leading causes of cancer-related deaths; thus, it is important to detect it as early as possible. Obesity is thought to be linked to a large rise in the CRC incidence as a result of bad dietary choices, such as a high intake of animal fats. Fatty acid-binding proteins (FABPs) are a set of molecules that...

Background Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. Methods RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (prim...

DNA repair promotes the progression and recurrence of glioblastoma (GBM). However, there remain no effective therapies for targeting the DNA damage response and repair (DDR) pathway in the clinical setting. Thus, we aimed to conduct a comprehensive analysis of DDR genes in GBM specimens to understand the molecular mechanisms underlying treatment re...

Background: Proper guidance of neuronal axons to their targets is required to assemble neural circuits during the development of the nervous system. However, the mechanism by which the guidance of axonal growth cones is regulated by specific intermediaries activated by receptor signaling pathways to mediate cytoskeleton dynamics is unclear. Vav pr...

Breast cancer is a complex disease, and several processes are involved in its development. Therefore, potential therapeutic targets need to be discovered for these patients. Proteasome 26S subunit, ATPase gene (PSMC) family members are well reported to be involved in protein degradation. However, their roles in breast cancer are still unknown and n...

Breast cancer is a heterogeneous disease involving complex interactions of biological processes; thus, it is important to develop therapeutic biomarkers for treatment. Members of the dipeptidyl peptidase (DPP) family are metalloproteases that specifically cleave dipeptides. This family comprises seven members, including DPP3, DPP4, DPP6, DPP7, DPP8...

Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies...

To assemble the nervous system's functional circuits, the neuronal axonal growth cones must be precisely guided to their proper targets, which can be achieved through cell-surface guidance receptor activation by ligand binding in the periphery. We investigated the function of paxillin, a focal adhesion protein, as an essential growth cone guidance...

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 induces severe infection, and it is responsible for a worldwide disease outbreak starting in late 2019. Currently, there are no effective medications against coronavirus. In the present study, we utilized a holistic bioinformatics approach to study gene signatures of SARS-CoV- and SARS-CoV-...

Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant o...

In seminiferous epithelium, tight junctions (TJs) between adjacent Sertoli cells constitute the blood-testis barrier and must change synchronically for germ cells to translocate from the basal to the adluminal compartment during the spermatogenic cycle. Rho GTPase activation through stimulation with specific L-selectin ligands has been proposed to...

Background Promyelocytic leukemia zinc finger (Plzf), a transcriptional regulator involved in a lot of important biological processes during development, has been implied to maintain neural stem cells and inhibit their differentiation into neurons. However, the effects of Plzf on brain structures and functions are still not clarified. Results We s...

Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was repo...

Glioblastoma (GBM) is the most aggressive type of brain tumor, with strong invasiveness and a high tolerance to chemotherapy. Despite the current standard treatment combining temozolomide (TMZ) and radiotherapy, glioblastoma can be incurable due to drug resistance. The existence of glioma stem-like cells (GSCs) is considered the major reason for dr...

Axonal growth cones are guided by molecular cues in the extracellular environment. The mechanisms of combinatorial integration of guidance signals at the growth cone cell membrane are still being unravelled. Limb-innervating axons of vertebrate spinal lateral motor column (LMC) neurons are attracted to netrin-1 via its receptor, Neogenin, and are r...

Background: The small population of glioma stem-like cells (GSCs) contributes to tumor initiation, malignancy, and recurrence in glioblastoma. However, the maintenance of GSC properties in the tumor microenvironment remains unclear. In glioma, non-neoplastic cells create an inflammatory environment and subsequently mediate tumor progression and ma...

During brain development, the expression of promyelocytic leukemia zinc finger (Plzf) in neural stem cells is precisely controlled to maintain the balance between neural stem cell self-renewal and differentiation. However, the mechanism underlying transcriptional regulation of Plzf in neural stem cell is still unclear. Herein, using P19 embryonal c...

Axonal growth cones are guided by molecular cues in the extracellular environment. The mechanisms of combinatorial integration of guidance signals at the growth cone cell membrane are still being unravelled. Limb-innervating axons of vertebrate spinal lateral motor column (LMC) neurons are attracted to netrin-1 via its receptor, Neogenin, and are r...

Background: The brain predominantly expressed RING finger protein, Znf179, is known to be important for embryonic neuronal differentiation during brain development. Downregulation of Znf179 has been observed in motor neurons of adult mouse models for amyotrophic lateral sclerosis (ALS), yet the molecular function of Znf179 in neurodegeneration has...

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The accumulation of reactive oxygen species (ROS) commonly occurs during normal aging and during some acute/chronic progressive disorders. In order to avoid oxidative damage, scavenging of these radicals is important. Previously, we identified zinc finger protein 179 (Znf179) as a neuroprotector that increases antioxidant enzymes against superoxide...

Background The development of a functioning nervous system requires precise assembly of neuronal connections, which can be achieved by the guidance of axonal growth cones to their proper targets. How axons are guided by signals transmitted to the cytoskeleton through cell surface‐expressed guidance receptors remains unclear. We investigated the fun...

The precise assembly of a functional nervous system relies on the guided migration of axonal growth cones, which is made possible by signals transmitted to the cytoskeleton by cell surface-expressed guidance receptors. We investigated the function of ephexin1, a Rho guanine nucleotide exchange factor, as an essential growth-cone guidance intermedia...

Acquisition of temozolomide (TMZ) resistance is a major factor leading to the failure of glioblastoma (GBM) treatment. The exact mechanism by which GBM evades TMZ toxicity is not always related to the expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), and so remains unclear. In this study, TMZ-resistant variants de...

Malignant glioblastoma multiforme (GBM) is an aggressive brain tumor with strong local invasive growth and a poor prognosis. One probable way to manipulate GBM cells toward a less invasive status is to reprogram the most malignant GBM cells to a more differentiated and less oncogenic phenotype. Herein, we identified a novel role of a RING finger pr...

Netrin1 has been proposed to act from the floor plate (FP) as a long-range diffusible chemoattractant for commissural axons in the embryonic spinal cord. However, netrin1 mRNA and protein are also present in neural progenitors within the ventricular zone (VZ), raising the question of which source of netrin1 promotes ventrally directed axon growth....

After sudden traumatic brain injuries, secondary injuries may occur during the following days or weeks, which leads to the accumulation of reactive oxygen species (ROS). Since ROS exacerbate brain damage, it is important to protect neurons against their activity. Zinc finger protein 179 (Znf179) was shown to act as a neuroprotective factor, but the...

Antisera, recombinant proteins, and quantification values. (A) Table listing all antibodies and recombinant proteins used. (B) Values of quantifications in main figures. (C) Values of quantifications in figure supplements. DOI: http://dx.doi.org/10.7554/eLife.10841.019

During neural circuit assembly, axonal growth cones are exposed to multiple guidance signals at trajectory choice points. While axonal responses to individual guidance cues have been extensively studied, less is known about responses to combination of signals and underlying molecular mechanisms. Here, we studied the convergence of signals directing...

It has been suggested that autophagy plays pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug that causes long-term serotonergic neurotoxicity in the brain. Apoptosis and necrosis have been implicated in MDMA-induced neurotoxicity, but the ro...

Axonal guidance involves extrinsic molecular cues that bind growth cone receptors and signal to the cytoskeleton through divergent pathways. Some signaling intermediates are deployed downstream of molecularly distinct axon guidance receptor families, but the scope of this overlap is unclear, as is the impact of embryonic axon guidance fidelity on a...

Repulsive Eph forward signaling from limb-derived ephrins guides the axons of lateral motor column (LMC) motor neurons. LMC axons also express ephrinAs, while their EphA receptors are expressed in the limb mesenchyme. In vitro studies have suggested that reverse signaling from limb-derived EphA4 to axonal ephrinAs might result in attraction of LMC...

Axon guidance receptors guide neuronal growth cones by binding in trans to axon guidance ligands in the developing nervous system. Some ligands are coexpressed in cis with their receptors, raising the question of the relative contribution of cis and trans interactions to axon guidance. Spinal motor axons use Eph receptors to select a limb trajector...

Expression of RALDH2, RC2, and Cadherins in Dab1 mutants. (A–L) Protein expression in lumbar spinal cord of e12.5 embryos. Foxp1 expression highlights LMC neurons; LMCm (M) neurons are Foxp1+ Isl1+, LMCl (L) neurons are Foxp1+ Isl1−. In Dab1 mutants, RALDH2 (A–F) and RC2 (G–L) distribution is unchanged when compared to control embryos. (M–X) Detect...

Quantification of motor neurons in Dab1 and Reln mutant embryos. (A, C) Quantification of LMC motor neuron numbers in e12.5 Dab1, Reln, and wild type (wt) littermate embryos expressed as the average number of total Foxp1+ LMC neurons per 12 µm section (# Foxp1+/section). LMC neuron numbers are not significantly different in mutants when compared to...

Expression of Dab1 and Reelin in e10.5 mouse and Dab1, Reelin, VLDLR, and ApoER2 in the chick spinal cord. (A–L) Detection of Isl1, Lhx1/5, Foxp1, and Dab1 in cervical (A–D) and lumbar spinal cord (E–H) and Reelin in cervical spinal cord (I–L). Dab1 is expressed in Foxp1+ LMC neurons, while Reelin expression is restricted to a small domain dorsal t...

Cell autonomous requirement for Dab1 signaling in LMCl migration. (A) Quantification of LMC motor neurons electroporated with LacZ or Dab15YF and LacZ expression plasmids in chick HH St 29 embryos, expressed as the average number of the total LacZ+ LMC neurons per 12 µm section (# LacZ+ MN/section). The difference in numbers between control and exp...

Isl1 is required for the specification of LMCm position. (A–D, F–I) Detection of LacZ, Foxp1, and Lhx1/5 protein in LMCm (Foxp1+ Lhx1/5−) and LMCl (Foxp1+ Lhx1/5+) neurons in lumbar spinal cord of chick HH St 29 embryos electroporated with LacZ (A–E) or [Isl1]siRNA and LacZ expression plasmids (F–J). Arrowheads point to electroporated LMCm neurons....

Antibodies used in this study. (A) Primary antibodies, (B) fluorochrome-conjugated secondary antibodies. DSHB: Developmental Studies Hybridoma Bank, developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa City, IA 52242. (0.09 MB DOC)

Supplemental data and supplemental materials and methods. (0.05 MB DOC)

Characterisation of Dab1 and Reelin mutants. (A–F) Loss of Dab1 immunoreactivity (arrowheads) in the lumbar spinal cord of an e12.5 Dab1 mutant embryo (D–F) compared to a control littermate (A–C). LMCl (L) neurons are Foxp1+ Isl1− and LMCm (M) neurons are Foxp1+ Isl1+. (G–L) Loss of Reln protein immunoreactivity (arrows) in the lumbar spinal cord o...

Position of LMC neurons in electroporated chick embryos. n: number of embryos analysed; N: total numbers of neurons counted; p values for position of experimental versus control neurons are from randomized Hotelling's T2 test under unequal variances. a Values are ± standard deviation of the mean; b only electroporated, LacZ+, or GFP+ LMC neurons we...

Position of LMC neurons in Dab1 and Reln mutants. n: number of embryos analysed; N: total numbers of neurons counted; p values for position of mutant versus littermate wild type neurons are from the randomized Hotelling's T2 test under unequal variances. a Values are ± standard deviation of the mean. (0.04 MB DOC)

Position of LMC neurons in Lhx1 mutants. LMCm (A), LMCl and LMCl* (B) position analysis. n: number of embryos analyzed; N: total numbers of neurons counted; p values for position versus littermate Lhx1 +/−, Randomization Hotellings T2 test under unequal variances; p′ values for position LMCl* versus LMCl same genotype, Randomization Hotellings T2 t...

Quantification of Dab1 and LMC neuronal identity in embryos over-expressing Dab1. (A) Quantification of LMCm (Isl1+ Foxp1+) and LMCl (Foxp1+ Isl1−) neuron numbers in the lumbar spinal cord of chick HH St 29 embryos expressing GFP or Dab1::GFP, expressed as the percentage of total motor neurons (Foxp1+ MNs (%)). The difference between experimental a...

Normal Hoxa5, Hoxc6, Reelin, and Chx10 expression in Hb9::Foxp1 transgenics and Foxp1 mutants. (A, D, G, J) Hoxa5 and Hoxc6 protein detection in cervical spinal cord of Hb9::Foxp1 (D), Foxp1 mutant (J), and control littermate (A, G) e12.5 embryos. (B, E, H, K) Foxp1 and Hb9 detection in cervical spinal cord of Hb9::Foxp1 (E), Foxp1 mutant (K), and...

Isl1 is sufficient to regulate Dab1 mRNA expression. (A–L, N–Y) LacZ, Isl1, Lhx1, and Dab1 mRNA detection in chick HH St 28–30 embryos electroporated with LacZ (A–F), Isl1 and LacZ expression plasmids (G–L), GFP (N–S), or [Isl1]siRNA and GFP expression plasmid (T–Y). In embryos electroporated with Isl1, Dab1 is downregulated on the electroporated s...

Variability of LMCl neuron location in Lhx1 mutants. Superimposed spinal cord position of LMCm (red), LMCl (green), and LMCl* (blue) neurons in consecutive sections of analyzed embryos highlights altered position of LMCl* neurons. Blue numbers indicate the fractions of LMCl* neurons expressed as percentage of Isl1− Foxp1+ motor neurons and the dash...

Author Summary Many areas of our nervous system are organized in a topographic manner, such that the location of a neuron relative to its neighbors is often spatially correlated with its axonal trajectory and therefore target identity. In this study, we focus on the spinal myotopic map, which is characterized by the stereotyped organization of moto...

Signal relay by guidance receptors at the axonal growth cone is a process essential for the assembly of a functional nervous system. We investigated the in vivo function of Src family kinases (SFKs) as growth cone guidance signaling intermediates in the context of spinal lateral motor column (LMC) motor axon projection toward the ventral or dorsal...