Auricles Anomalies in Patients With a TCF12 Gene Mutation.

Craniostenosis is a morphological anomaly affecting about 0.5 of 1000 births and one third of the cases are of genetic origin. Among the syndromes responsible for craniostenosis, there is the Saethre-Chotzen syndrome due to a mutation of the TWIST 1 gene located on chromosome 7. This polymalformative syndrome classically includes a particular morphology of the auricles. The penetrance is variable and results in a phenotypic variability at the origin of "Saethre-Chotzen like" clinical pictures for which the TWIST 1 gene mutation is sometimes not found. Recently, the TCF 12 gene has been implicated in some of these cases. Among the multiple facial malformations, we have carefully examined the particular morphology of the auricle of these patients. The authors found several abnormalities in patients with a TCF 12 gene mutation, namely a thickened and hammered upper pole of the helix, a narrow concha without crux cymbae and a thickened lobe. These morphological features may guide the diagnosis and allow an earlier search for a TCF 12 gene mutation.

Efficacy of lanreotide 120 mg primary therapy on tumour shrinkage and ophthalmologic symptoms in acromegaly after 1 month.

INTRODUCTION: Few studies have attempted to evaluate the early efficacy of first-generation somatostatin analogues in somatotroph macroadenomas. OBJECTIVE: To investigate the short-term efficacy of primary therapy with lanreotide 120 mg at 1 and 3 months on tumour shrinkage and ophthalmologic symptoms in newly diagnosed patients with acromegaly. DESIGN AND PATIENTS: This single-centre retrospective study included 21 patients with de novo acromegaly resulting from pituitary macroadenoma, with optic chiasm compression (Grade ≤ 2) and/or cavernous sinus invasion, treated with a monthly injection of lanreotide 120 mg. Clinical, hormonal, ophthalmologic and magnetic resonance imaging scan evaluations were conducted after the first and the third months of treatment. RESULTS: Tumour volume reduction was more pronounced at 1 month; mean volume change: -31.4 ± 19.5%, p < .0001 than between the first and third month of treatment; mean volume reduction: -20.6 ± 13.4%, p = .0009. The mean volume change between baseline and the third month was - 46.4 ± 21.6, (p < .0001). A significant volume reduction (≥25%) was observed in 61.9% of individuals (13/21) at the first month. Among 14 individuals with optic chiasm compression and visual field defects, visual field normalization or improvement were observed in seven cases (50%), stabilization in four cases (28.5%), and mild worsening in three cases (21.4%) at 1 month. The decrease in growth hormone and IGF-1 serum values was significant at 1 month. CONCLUSIONS: Primary treatment with lanreotide 120 mg in patients with somatotroph macroadenomas provides early significant tumour shrinkage with rapid improvement of visual symptoms at the end of the first month in 50% of patients.

The legal challenges to the diagnosis of shaken baby syndrome or how to counter 12 common fake news.

BACKGROUND: The shaken baby syndrome (SBS) is a common cause of severe traumatic lesions in infants. Although well established for almost five decades, SBS and its diagnosis are becoming more and more aggressively challenged in courts. These challenges feed on the scientific debate and controversies regarding the pathophysiology and the differential diagnoses, scientific uncertainty being readily exploited by specialized barristers. MATERIAL AND METHODS: In the present review, we analyze the most common challenges to the concept of SBS and its diagnosis, as well as the scientific evidence available to counter these challenges, the differential diagnoses, and how SBS can be diagnosed with confidence. RESULTS: We found that the pathophysiology of SBS is well documented, with stereotyped descriptions by perpetrators, in good correlation with experimental studies and computer models. SBS is a well-defined clinico-pathological entity with a characteristic constellation of lesions; with a rigorous evaluation protocol, its diagnosis can be made rapidly and with excellent accuracy beyond a reasonable doubt. CONCLUSION: It is important that medical experts master an extensive knowledge regarding the pathophysiology of the lesions of SBS, in particular infantile subdural hematomas, as well as other CSF-related conditions. This emphasizes the role that pediatric neurosurgeons should play in the clinical and medicolegal management of these patients.

Answer to Lynøe: Interesting data about confessions and abusive head trauma, but suboptimal analysis.

The authors of the cited paper respond to the critics formulated by a Swedish leading expert regarding methodology shortcomings of our study "Confessed versus denied inflicted head injuries in infants: similarities and differences." They admit some methodological limitations but maintain their conclusions that the diagnosis was correct in the confession and denial groups and that the denial was more difficult in the more severe cases.

Spinal lesions caused by abusive trauma in young children.

BACKGROUND AND PURPOSE: Spinal lesions are increasingly recognized as an integral part of the child abuse spectrum; however, the description of lesions, their biomechanics, true incidence, clinical impact, and medicolegal implications are poorly understood. MATERIAL AND METHODS: We report from the literature and our personal experience on abusive spinal lesions (ASL) in children under 3 years, compared with cases of abusive head injuries (AHI) without spinal lesions on the one hand and with accidental spinal lesions on the other. RESULTS: Between 2002 and 2021, we collected 12 observations of ASL, 4 male and 8 female. These were compared with 338 cases of infants having AHI without ASL and 18 cases of accidental spinal trauma in the same age group. Fractures were found in 10 cases of ASL: wedge fracture in 9, and complete disruption with paraplegia in one, which required emergency reduction and stabilization with a good motor recovery. Two patients had intraspinal hemorrhagic lesions without fracture, associated in one case with tetraplegia which contributed to the fatal outcome. ASL affected girls more often and had a more severe clinical presentation; more than half of ASL involved the lumbar levels, which were unaffected in accidental traumas. CONCLUSIONS: ASL are not exceptional, and their presence corroborates cranial lesions indicating child abuse. Two etiologies emerge from this study: wedge fractures and cervical spinal cord lesions caused by shaking and the rare thoraco-lumbar dislocation indicating a particularly violent assault. Systematic MRI study of the spine is warranted in cases of child abuse.

Confessed versus denied inflicted head injuries in infants: similarities and differences.

BACKGROUND AND PURPOSE: Abusive head injuries (AHI), and in particular shaken baby syndrome (SBS), are common causes of mortality and morbidity in infants. Although SBS is a well-established entity, based on clinical experience and experimental data, and confirmed by the perpetrators' confessions, a growing number of publications challenge the diagnostic criteria, and even the validity of the perpetrators' confession. We decided to study AHI in infants and compare cases with and without confession. MATERIAL AND METHODS: We collected prospectively all cases of infantile traumatic head injuries hospitalized in our institution between 2001 and 2021. From this database, we selected victims of AHI, comparing cases for which the perpetrator confessed during police inquiry ("confession" group) versus cases without confession ("denial" group). RESULTS: We studied 350 cases of AHI in infants; 137 of these (39.1%) were confessed. We found no statistically significant difference between the two groups regarding the child's previous history, as well as the personality and previous history of the caretakers. However, the "confession" group showed significantly more severe clinical presentation, cerebral lesions, retinal hemorrhages, and a more pejorative outcome. CONCLUSIONS: We conclude that the diagnosis of AHI was confirmed by the confession in a large number of cases, indicating that the diagnostic criteria of AHI are robust. We also found that denial, although possibly sincere, was likely ill-founded, and that the perpetrators' decision to confess or deny was markedly influenced by the severity of the inflicted lesions.

Synostosis of the lambdoid suture: a spectrum.

PURPOSE: Lambdoid synostosis (LS) is a rare condition, which is either isolated; associated with sagittal synostosis, the "Mercedes-Benz" syndrome (MBS); or with synostosis of the coronal sutures (oxycephalic form). In addition, LS is part of the phenotype of a growing number of genetic diseases. The nosology, pathophysiology, and management are controversial. We decided to review our experience with LS. METHODS: We reviewed retrospectively pediatric cases of LS proved on CT-scanner, isolated or associated with other conditions, followed in our craniofacial center during the last 15 years, regarding clinical presentation, anatomical lesions, syndromic associations, surgical management, and outcome. RESULTS: We reviewed 48 cases: 6 isolated LS, 22 MBS, and 20 oxycephalic. A syndromic context was present in 72% (up to 80% of oxycephalic cases), and faciostenosis was present in 23%, mostly oxycephalic cases (40%). Transverse sinus agenesis was found in 61% of documented patients. A total of 31% of children had a dystocic birth, up to 45% of MBS. Decompressive craniectomy or cranioplasty was needed in a majority of patients, often young infants, while posterior fossa decompression was mostly performed in older children. CONCLUSION: LS is rarely isolated and non syndromic; most cases are found in a wide spectrum of diseases, and LS is often associated with sagittal or coronal synostosis. Genetic evaluation is mandatory for LS; conversely, geneticists may require neurosurgical advice for LS in an increasing number of very rare diseases. The surgical management of LS should be tailored according to clinical presentation, age, and syndromic context.

Morphological and surgical results in sagittal synostosis: early craniectomy versus later cranioplasty.

BACKGROUND AND PURPOSE: Morphological correction is one of the main aims of surgery for sagittal synostosis (SSO). Different surgical techniques have been developed; however, few studies have compared the different surgical protocols. The morphological outcome is poorly documented, because a consensual evaluation tool is lacking. MATERIAL AND METHODS: We performed a prospective study of children operated for SSO in our institution. Children were operated whenever possible at 4 months for craniectomy; by default, children underwent cranioplasty at or after 9 months. The morphological outcome of all children was evaluated using traditional craniometry with head circumference (HC) and the cephalic index (CI), and with the Rotterdam scaphocephaly morphology score (RSMS), a total of semi-quantitative assessments of morphological hallmarks. RESULTS: Craniectomy was significantly associated with a shorter operation time and hospital stay, and a better impact on HC and CI measurements, compared with cranioplasty. The RSMS was markedly improved after surgery in both groups; however, we found no significant difference in improvement between the two groups. Although the transfusion rate and the prevalence of developmental delay were lower in the craniectomy group, and reoperations for calvarial lacunae or complex craniosynostosis occurred only this group, these differences were not significant. CONCLUSIONS: Our results support early surgery with craniectomy whenever possible; however, cranioplasty at a later age is a very acceptable by-default indication. In addition to classical craniometry, morphological evaluation using the RSMS or a similar quantitative scale appears highly desirable for future studies.

Linear craniectomy for early posterior decompression in craniosynostoses: technique and results.

INTRODUCTION: Early decompressive posterior linear craniectomy (PLC) can be indicated in very young infants with complex multisuture synostosis, which often involve the lambdoid suture (LS). The literature data on the surgical technique and its results are scarce. MATERIAL AND METHODS: Based on our experience with PLC during the last 10 years, we detail our surgical technique for PLC, the possible pitfalls, and complication avoidance. RESULTS: We review seven observations, 5 girls and 2 boys, 6 of these with identified mutations, operated for PLC at a mean age of 3.19 months (6 days to 6.1 months). One patient died of unexplained cardiac arrest on postoperative day two, the others had a favorable outcome with good development and no visual loss. Three of these required additional cranioplasty at a later age, one of these with craniofacial distraction. DISCUSSION: PLC can be a salvage operation in very young patients with complex synostosis involving the LS, and with proper preparation and careful technique, allows favorable outcome. The approach must be versatile in order to anticipate further surgeries in these complex, most often syndromic cases.

Fusiform dilatation of internal carotid artery after pterional but not subfrontal craniotomy in 6 patients.

PURPOSE: Our study aimed to evaluate potential risk factors for the development of FDICA after suprasellar tumor resection. MATERIALS AND METHOD: After reviewing all cases of pediatric patients who benefited from a suprasellar lesion resection in our two medical institutions, we found 6 patients with a FDICA. Surgical approach strategy (pterional or subfrontal approaches) was noted. Postoperative cranial MRI was performed in each patient 3 months after surgery and every year. When a FDICA occurred, MRI was performed 6 months after the diagnosis and 1 year later to detect any progression. RESULTS: There were 6 males with a mean age at treatment of 11 years (6 to 15). Pterional approach was performed in these 6 patients. At the 2 institutions, we have done at least 50 pterional craniotomies for suprasellar lesion resection. No FDICA was reported after subfrontal approach in 27 consecutive pediatric patients operated on from a craniopharyngioma. The delay between the surgery and the diagnosis of the FDICA was 9 months (3 to 17 months). No symptoms related to the FDICA were recorded. The mean maximal diameter of the aneurysm was 14 mm (10 to 21). ICA bifurcation was involved in 2 cases. Asymptomatic FDICA progression was noted in 2 cases but no treatment was proposed. CONCLUSION: The pathogenesis of FDICA is unclear, and might involve arterial wall necrosis caused by postoperative arachnoid fibrosis which might be worsened by the pterional approach.

Does the hip positioning matter for oblique lumbar interbody fusion approach? A morphometric study.

PURPOSE: To evaluate whether left hip positioning widened the access corridor using oblique lateral interbody fusion (OLIF) approach during right lateral decubitus (RLD). METHODS: Ten healthy adult volunteers underwent a T2 lumbosacral MRI (1.5 T) in the supine position, RLD position with left hip in extension and then in flexion. L2-L3 to L5-S1 disc spaces were identified. At each level, left psoas surface (in cm2), access corridor (in mm) and vessel movement were calculated in the three positions. Paired t test was used for comparison. RESULTS: The mean surface of the left psoas ranged from 7.83 to 17.19 cm2 in the three positions (p > 0.05). From L2-3 to L4-5, in RLD, when the left hip shifted from extension to flexion, nor the access corridor nor vessel movements were significantly different. When the volunteers shifted from supine to RLD position with hip in extension, arteries moved 3.66-5.61 mm to the right (p < 0.05 at L2-3, L3-4 and L5-S1), while the venous structures moved 0.92-4.96 mm (p < 0.05 at L2-3) to the right. When the position shifted from supine to RLD with hip in flexion, the arterial structures moved 0.47-4.88 mm (p < 0.05 at L2-3 and L3-4) to the right, while the venous structures moved - 0.94 to 4.13 mm (p < 0.05 at L2-3 and L3-4) to the right. CONCLUSION: Hip positioning was not associated with a significant widening of the surgical corridor. To perform OLIF, we advocate for RLD position with left hip in extension to move away the vascular structures and reduce the psoas volume. These slides can be retrieved under Electronic Supplementary Material.

RhoA Inhibitor Treatment At Acute Phase of Spinal Cord Injury May Induce Neurite Outgrowth and Synaptogenesis.

The therapeutic use of RhoA inhibitors (RhoAi) has been experimentally tested in spinal cord injury (SCI). In order to decipher the underlying molecular mechanisms involved in such a process, an in vitro neuroproteomic-systems biology platform was developed in which the pan-proteomic profile of the dorsal root ganglia (DRG) cell line ND7/23 DRG was assessed in a large array of culture conditions using RhoAi and/or conditioned media obtained from SCI ex vivo derived spinal cord slices. A fine mapping of the spatio-temporal molecular events of the RhoAi treatment in SCI was performed. The data obtained allow a better understanding of regeneration/degeneration induced above and below the lesion site. Results notably showed a time-dependent alteration of the transcription factors profile along with the synthesis of growth cone-related factors (receptors, ligands, and signaling pathways) in RhoAi treated DRG cells. Furthermore, we assessed in a rat SCI model the in vivo impact of RhoAi treatment administered in situ via alginate scaffold that was combined with FK506 delivery. The improved recovery of locomotion was detected only at the early postinjury time points, whereas after overall survival a dramatic increase of synaptic contacts on outgrowing neurites in affected segments was observed. We validate these results by in vivo proteomic studies along the spinal cord segments from tissue and secreted media analyses, confirming the increase of the synaptogenesis expression factors under RhoAi treatment. Taken together, we demonstrate that RhoAi treatment seems to be useful to stimulate neurite outgrowth in both in vitro as well in vivo environments. However, for in vivo experiments there is a need for sustained delivery regiment to facilitate axon regeneration and promote synaptic reconnections with appropriate target neurons also at chronic phase, which in turn may lead to higher assumption for functional improvement.

Evaluation of the relevance of surgery in a retrospective case series of patients who underwent the surgical treatment of a symptomatic spine metastasis from lung cancer.

BACKGROUND: The management of spine metastases is an increasing concern for spine surgeons. When considering surgery, it is crucial to ensure that its iatrogenic effects will not exceed its potential benefits, particularly in frail patients with short life expectancy. Among all prognostic factors, the primary site of cancer is the most important, lung cancer being the poorest. Although surgery has shown its effectiveness in the management of spine metastases, there is a lack of studies focusing on lung cancer alone. PURPOSE: To assess the effectiveness and safety of surgery in the management of symptomatic spine metastases from lung cancer. METHODS: We retrospectively reviewed all patients (n = 53) who underwent surgery for spine metastasis from lung cancer at the Lille University Hospital between January 2005 and December 2011. Patients for whom surgery was effective to restore or preserve ambulation, to relieve pain, and to ensure stability without severe complication were considered "surgical success". RESULTS: No patient was lost to follow-up and vital status data were available for all patients. The median survival was 2.1 months and was not influenced by the surgical success (p = 0.1766). We reported seven major complications in seven patients, including three epidural haematoma, two massive pulmonary embolisms and two deaths from cardiopulmonary failure. The surgical success rate was 49 % and on univariate analysis, the factors that have influenced the postoperative outcome were the KPS (p < 0.001), the Frankel grade (p = 0.0217) and the delay between the cancer diagnosis and the occurrence of spine metastases (p = 0.0216). CONCLUSION: A strict patient selection is required to limit the iatrogenic effect of surgery, which may alter the quality of life of these frail patients with limited life expectancy.

Microsurgical management of recurrent intracranial aneurysm after endovascular treatment: a series of 60 consecutive patients.

OBJECTIVE: The aim of this study was to evaluate the morbidity associated with microsurgical treatment in patients with a recurrent aneurysm to improve their surgical management. METHODS: From 2012 to 2022, among the 3128 patients with ruptured or unruptured intracranial aneurysms managed at the authors' institution, 954 patients were treated by a microsurgical procedure. Of these 3128 patients, 60 consecutive patients (6.3%) who had a recurrent microsurgically treated aneurysm after previous endovascular treatment were included in this study. Additional microsurgical treatment was considered in case of progressive remnant growth or significant aneurysm recurrence. Intraoperative and postoperative complications were noted. Early (< 7 days) and long-term clinical and radiological monitoring were performed. Good functional outcome was considered as a modified Rankin Scale score < 3. RESULTS: The mean age at initial treatment was 45 years (range 26-65 years). The mean delay between the first treatment and microsurgical treatment of the recurrence was 64 months (range 2 days-296 months). The mean size of the fundus recurrence was 5 mm, and the mean size of the neck recurrence was 4.6 mm. Five patients (8.3%) presented with subarachnoid hemorrhage associated with rupture of the recurrent aneurysm. Three patients died (6%) of aneurysm rupture and/or intensive care complications. The total morbidity rate associated with the microsurgical procedure was 14.5% (8/55) in patients with unruptured recurrent aneurysms. Among these patients, postoperative definitive complications (ischemic lesions) directly related to the microsurgical procedure were present in 3 patients (5.5%). Intraoperative rupture was recorded in these 3 patients. In the 54 surviving patients with unruptured recurrent aneurysms, good functional outcome was noted in 49 (91%). Poor functional outcome was significantly associated with intraoperative rupture. CONCLUSIONS: Microsurgery remains an effective therapeutic option for recurrent intracranial aneurysms. However, in the authors' experience, postoperative morbidity is higher than in patients with nonrecurrent aneurysms. Therefore, a pretherapeutic multidisciplinary evaluation is mandatory to reduce the potential morbidity associated with the retreatment as much as possible. When endovascular occlusion of the aneurysm requires both stenting and coiling, alternative microsurgical treatment should be carefully evaluated, as microsurgical clipping will become much more challenging in cases of aneurysm recurrence.

CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

Selective clipping of giant anterior communicating artery aneurysms remains a reliable therapeutic option.

BACKGROUND: Giant anterior communicating artery (AcomA) aneurysm represent a significant surgical challenge. Our study aimed to discuss the therapeutic strategy in patients with a giant AcomA aneurysm treated by selective neck clipping through a pterional approach. METHODS: Among all operated patients from an intracranial aneurysm between January 2015 and January 2022 (n = 726) in our institution, three patients with a giant AcomA aneurysm treated by neck clipping were included. Early (<7days) outcome was noted. Early postoperative CT scan was performed in all patients to detect any complications. Early DSA was also performed to confirm giant AcomA aneurysm exclusion. The mRS score was recorded 3 months after treatment. The mRS≤ 2 was considered as a good functional outcome. Control DSA was performed one year after treatment. RESULTS: In the three patients, after a large frontopterional approach, a selective exclusion of their giant AcomA aneurysm was obtained after a partial pars orbitalis of the inferior frontal gyrus resection. Ischemic lesion was noted in 1 patient and chronic hydrocephalus in 2 patients with ruptured aneurysm. The mRS score after 3 months was good in 2 patients. Long term complete occlusion of the aneurysm were noted in the three patients. CONCLUSION: Selective clipping of a giant AcomA aneurysm is a reliable therapeutic option after a careful evaluation of local vascular anatomy. An adequate surgical exposure is frequently obtained through an enlarged pterional approach with an anterior basifrontal lobe resection, especially in an emergency situation and/or in case of high position of anterior communicating artery.

Unruptured cerebral arteriovenous malformation in children: Outcome in treated and untreated patients.

BACKGROUND: The management of unruptured cerebral arteriovenous malformation (URCAVM) is highly controversial; however, data regarding URCAVM in children are scarce. MATERIAL AND METHODS: We retrospectively reviewed consecutive children followed for URCAVM in our department between 2001 and 2021. RESULTS: Out of 36 patients, 12 were initially managed by observation, and 24 underwent first-line treatment: 8 by microsurgery, 10 by radiosurgery, 2 by embolization, and 4 by combined treatment. Mean follow-up of the whole group was 63months. Complete cure of the malformation was obtained in 14 patients (58%) in the treatment group: 8/8 in the microsurgery group, 5/10 in the radiosurgery group, 1/4 in the combined treatment group, and none in the embolization group. Two of the initially non-treated patients presented cerebral hemorrhage, with significant neurological consequences. In the treatment group, 5 patients presented new neurological deficits, only 1 of which, however, was functionally significant. Headache improved in 11 cases, mostly in the treatment group. Overall, 6 patients in the treatment group became asymptomatic, versus none in the observation group. CONCLUSIONS: The treatment of URCAVM is a reasonable option in many pediatric cases, considering the cumulative risk of cerebral hemorrhage during the child's lifetime, as well as the symptoms specific to URCAVM. Microsurgery, when feasible, offers the best functional results and control of the AVM; however, the risk-benefit ratio should be weighed on a case-by-case basis. More studies will be needed to inform treatment decisions in pediatric URCAVM.

Heimdall, an alternative protein issued from a ncRNA related to kappa light chain variable region of immunoglobulins from astrocytes: a new player in neural proteome.

The dogma "One gene, one protein" is clearly obsolete since cells use alternative splicing and generate multiple transcripts which are translated into protein isoforms, but also use alternative translation initiation sites (TISs) and termination sites on a given transcript. Alternative open reading frames for individual transcripts give proteins originate from the 5'- and 3'-UTR mRNA regions, frameshifts of mRNA ORFs or from non-coding RNAs. Longtime considered as non-coding, recent in-silico translation prediction methods enriched the protein databases allowing the identification of new target structures that have not been identified previously. To gain insight into the role of these newly identified alternative proteins in the regulation of cellular functions, it is crucial to assess their dynamic modulation within a framework of altered physiological modifications such as experimental spinal cord injury (SCI). Here, we carried out a longitudinal proteomic study on rat SCI from 12 h to 10 days. Based on the alternative protein predictions, it was possible to identify a plethora of newly predicted protein hits. Among these proteins, some presented a special interest due to high homology with variable chain regions of immunoglobulins. We focus our interest on the one related to Kappa variable light chains which is similarly highly produced by B cells in the Bence jones disease, but here expressed in astrocytes. This protein, name Heimdall is an Intrinsically disordered protein which is secreted under inflammatory conditions. Immunoprecipitation experiments showed that the Heimdall interactome contained proteins related to astrocyte fate keepers such as "NOTCH1, EPHA3, IPO13" as well as membrane receptor protein including "CHRNA9; TGFBR, EPHB6, and TRAM". However, when Heimdall protein was neutralized utilizing a specific antibody or its gene knocked out by CRISPR-Cas9, sprouting elongations were observed in the corresponding astrocytes. Interestingly, depolarization assays and intracellular calcium measurements in Heimdall KO, established a depolarization effect on astrocyte membranes KO cells were more likely that the one found in neuroprogenitors. Proteomic analyses performed under injury conditions or under lipopolysaccharides (LPS) stimulation, revealed the expression of neuronal factors, stem cell proteins, proliferation, and neurogenesis of astrocyte convertor factors such as EPHA4, NOTCH2, SLIT3, SEMA3F, suggesting a role of Heimdall could regulate astrocytic fate. Taken together, Heimdall could be a novel member of the gatekeeping astrocyte-to-neuroprogenitor conversion factors.

Astrocytes express aberrant immunoglobulins as putative gatekeeper of astrocytes to neuronal progenitor conversion.

Using multi-omics analyses including RNAseq, RT-PCR, RACE-PCR, and shotgun proteomic with enrichment strategies, we demonstrated that newborn rat astrocytes produce neural immunoglobulin constant and variable heavy chains as well as light chains. However, their edification is different from the ones found in B cells and they resemble aberrant immunoglobulins observed in several cancers. Moreover, the complete enzymatic V(D)J recombination complex has also been identified in astrocytes. In addition, the constant heavy chain is also present in adult rat astrocytes, whereas in primary astrocytes from human fetus we identified constant and variable kappa chains as well as the substitution lambda chains known to be involved in pre-B cells. To gather insights into the function of these neural IgGs, CRISPR-Cas9 of IgG2B constant heavy chain encoding gene (Igh6), IgG2B overexpression, proximal labeling of rat astrocytes IgG2B and targets identification through 2D gels were performed. In Igh6 KO astrocytes, overrepresentation of factors involved in hematopoietic cells, neural stem cells, and the regulation of neuritogenesis have been identified. Moreover, overexpression of IgG2B in astrocytes induces the CRTC1-CREB-BDNF signaling pathway known to be involved in gliogenesis, whereas Igh6 KO triggers the BMP/YAP1/TEAD3 pathway activated in astrocytes dedifferentiation into neural progenitors. Proximal labeling experiments revealed that IgG2B is N-glycosylated by the OST complex, addressed to vesicle membranes containing the ATPase complex, and behaves partially like CD98hc through its association with LAT1. These experiments also suggest that proximal IgG2B-LAT1 interaction occurs concomitantly with MACO-1 and C2CD2L, at the heart of a potentially novel cell signaling platform. Finally, we demonstrated that these chains are synthesized individually and associated to recognize specific targets. Indeed, intermediate filaments Eif4a2 and Pdia6 involved in astrocyte fate constitute targets for these neural IgGs. Taken together, we hypothese that neural aberrant IgG chains may act as gatekeepers of astrocytes' fate.