Abstract
BackgroundThe human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS). Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause.ResultsWe report sensory differences in Necdin deficient mice compared to wild type animals. These differences led us to investigate sensory neuron development in Necdin deficient mouse embryos. First, we describe the expression pattern of Necdin in developing DRGs and report a reduction of one-third in specified sensory neurons in dorsal roots ganglia and show that this neuronal loss is achieved by E13.5, when DRGs sensory neurons are specified. In parallel, we observed an increase of 41% in neuronal apoptosis during the wave of naturally occurring cell death at E12.5. Since it is assumed that Necdin is a P75NTR interactor, we looked at the P75NTR-expressing cell population in Necdin knock-out embryos. Unexpectedly, Necdin loss of function has no effect on p75NTR expressing neurons suggesting no direct genetic interaction between Necdin and P75NTR in this context.Although we exclude a role of Necdin in axonal outgrowth from spinal sensory neurons in early developmental stages; such a role could occur later in neuronal differentiation. Finally we also exclude an anti-proliferative role of Necdin in developing sensory neurons.ConclusionOverall, our data show clearly that, in early development of the nervous system, Necdin is an anti-apoptotic or survival factor.
Highlights
The human NECDIN gene is involved in a neurodevelopmental disorder, PraderWilli syndrome (PWS)
We have shown that Necdin is expressed through embryogenesis in postmitotic neurons [16], we hypothesized that a defect during the ontogeny of sensory neurons in Necdin deficient mice might result in a loss or Distance traveled Time spent in center (%) Entries in center Rearings
In an attempt to determine which class of specified Dorsal Root Ganglias (DRGs) neurons express Necdin, we examined the expression of the three tyrosine kinase receptors (Trk), TrkA, TrkB and TrkC; characterizing respectively Nerve Growth Factor (NGF) responding nociceptive neurons, BDNF responsive neurons and NT3 responsive proprioceptive neurons [24]
Summary
The human NECDIN gene is involved in a neurodevelopmental disorder, PraderWilli syndrome (PWS). A role in neuronal terminal differentiation, in neurite outgrowth and fasciculation was supported by a number of studies [8,11,12,13] This role is thought to implicate the Nerve Growth Factor (NGF) signalling pathway [8,11,12] and/ or a signalling pathway involving centrosomal function and cytoskeletal rearrangement [13]. Supporting these findings, a large variety of Necdin partners have been revealed using yeast two-hybrids or Ras Rescue Systems. Necdin cytoplasmic interactors (FEZ1, BBS4, NEFA and Nuc which are both Ca2+ binding proteins), or nuclear interactors such as cell-cycle proteins (E2F1, E2F2, p53) and neurotrophic receptors (p75NTR, TrkA) have been characterized
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
