Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination

Abstract

<jats:p>Disorders that disrupt myelin formation during development or in adulthood, such as multiple sclerosis and peripheral neuropathies, lead to severe pathologies, illustrating myelin’s crucial role in normal neural functioning. However, although our understanding of glial biology is increasing, the signals that emanate from axons and regulate myelination remain largely unknown. To identify the core components of the myelination process, here we adopted a microarray analysis approach combined with laser-capture microdissection of spinal motoneurons during the myelinogenic phase of development. We identified neuronal genes whose expression was enriched during myelination and further investigated hepatoma-derived growth factor-related protein 3 (HRP3 or HDGFRP3). HRP3 was strongly expressed in the white matter fiber tracts of the peripheral (PNS) and central (CNS) nervous systems during myelination and remyelination in a cuprizone-induced demyelination model. The dynamic localization of HPR3 between axons and nuclei during myelination was consistent with its axonal localization during neuritogenesis. To study this phenomenon, we identified two splice variants encoded by the <jats:italic>HRP3</jats:italic> gene: the canonical isoform HRP3-I and a newly recognized isoform, HRP3-II. HRP3-I remained solely in the nucleus, whereas HRP3-II displayed distinct axonal localization both before and during myelination. Interestingly, HRP3-II remained in the nuclei of unmyelinated neurons and glial cells, suggesting the existence of a molecular machinery that transfers it to and retains it in the axons of neurons fated for myelination. Overexpression of HRP3-II, but not of HRP3-I, increased Schwann cell numbers and myelination in PNS neuron–glia co-cultures. However, HRP3-II overexpression in CNS co-cultures did not alter myelination.</jats:p>

Hepatoma Derived Growth Factor Enhances Oligodendrocyte Genesis from Subventricular Zone Precursor Cells

“…HDGF is expressed and secreted by neurons (Zhou et al ., 2004); however, whether neuronally secreted HDGF is responsible for neuron-specific effects on OPCs remains to be addressed. Interestingly, another HDGF family member, HDGF-related protein 3 (HRP3), is enriched in CNS and peripheral nervous system (PNS) white matter tracts during myelination and remyelination (Kerman et al ., 2020). From the two isoforms of HRP-3, only the overexpression of the second isoform HRP3-II in PNS neurons increases Schwann cell numbers and myelination in neuron-glia co-cultures (Kerman et al ., 2020).…”

“…Interestingly, another HDGF family member, HDGF-related protein 3 (HRP3), is enriched in CNS and peripheral nervous system (PNS) white matter tracts during myelination and remyelination (Kerman et al ., 2020). From the two isoforms of HRP-3, only the overexpression of the second isoform HRP3-II in PNS neurons increases Schwann cell numbers and myelination in neuron-glia co-cultures (Kerman et al ., 2020). Our results showing HDGF exerts pro-proliferative and pro-differentiation effects on SVZ precursor cells support and extend this report.…”