FoxJ1 regulates spinal cord development and is required for the maintenance of spinal cord stem cell potential

Abstract

Development of the spinal cord requires dynamic and tightly controlled expression of numerous transcription factors. Forkhead Box protein J1 (FoxJ1) is a transcription factor involved in ciliogenesis and is specifically expressed in ependymal cells (ECs) in the adult central nervous system. However, using FoxJ1 fate-mapping mouse lines, we observed that FoxJ1 is also transiently expressed by the progenitors of other neural subtypes during development. Moreover, using a knock-in mouse line, we discovered that FoxJ1 is essential for embryonic progenitors to follow a normal developmental trajectory. FoxJ1 loss perturbed embryonic progenitor proliferation and cell fate determination, and resulted in formation of adult ECs having impaired stem cell potential and an inability to respond to spinal cord injury in both male and female animals. Thus, our study uncovers unexpected developmental functions of FoxJ1 in cell fate determination of subsets of neural cells and suggests that FoxJ1 is critical for maintaining the stem cell potential of ECs into adulthood.

Multiple steps mediate ventricular layer attrition to form the adult mouse spinal cord central canal

“…The ependymal cells that form the central canal in the adult mammalian spinal cord constitute a largely 50 quiescent stem cell niche (Adrian and Walker, 1962, Kraus-Ruppert et al, 1975, Alfaro-Cervello et al, 2012, Sabourin et al, 2009. These cells can be induced to re-enter the cell cycle in response to 52 extrinsic stimuli, including mechanosensory stimulation (Shechter et al, 2011), physical exercise (Krityakiarana et al, 2010), inflammation (Chi et al, 2006, Danilov et al, 2006 and injury (Adrian and 54 Walker, 1962, Frisen et al, 1995, Barnabe-Heider et al, 2010, Johansson et al, 1999, Li et al, 2016, Li et al, 2018, Meletis et al, 2008. Moreover, most of these stimuli appear to promote the generation 56 of new neurons and glial cells, consistent with in vitro studies of the differentiation potential of the spinal cord ependymal cell population (Weiss et al, 1996, Johansson et al, 1999, Li et al, 2016, Meletis et 58 al., 2008, Sabourin et al, 2009).…”

“…Moreover, most of these stimuli appear to promote the generation 56 of new neurons and glial cells, consistent with in vitro studies of the differentiation potential of the spinal cord ependymal cell population (Weiss et al, 1996, Johansson et al, 1999, Li et al, 2016, Meletis et 58 al., 2008, Sabourin et al, 2009). However, following spinal cord injury, central canal cells proliferate and migrate to the lesion site, but here differentiate into only glia (Barnabe-Heider et al, 2010, Li et al, 60 2016, Li et al, 2018, Meletis et al, 2008, Martens et al, 2002. These cells then contribute to scar tissue, many becoming astrocytes which reduce inflammation, but chronically inhibit axonal re-growth 62 (Warren et al, 2018), while others differentiate into oligodendrocytes, which can promote survival of nearby neurons and help to maintain the integrity of the injured spinal cord (Sabelstrom et al, 2013).…”

“…356 Intriguingly, this dissociation of the ventral-most cell population occurs concomitant with a 358 change in the expression pattern of Foxj1, the master regulator of the ciliogenesis programme (Choksi et al, 2014) and a mediator of migratory cell behaviour of spinal cord ependymal cells in response to 360 injury(Li et al, 2018). Foxj1 transcript and protein levels decline in the floor plate as ventral dissociation begins at E15.5 (compare ventral region in Figs 5A-D and 5Ha-Ib), but is upregulated in ventral 362 progenitors from E14.5 (Figs 5C-5G and 5Ha-5Lb) and expressed in the majority of central canal cells, although only at low-level in ventral-most cells at E18.5(Li et al, 2018). Together, these observations 364 identify a distinct dissociation event which resolves the ventral ventricular cell population into two anatomically distinct groups, the ventral central canal and the dissociated ventral-most floor plate.…”

Unlocking the paradoxical endogenous stem cell response after spinal cord injury

“…Indeed, the transgenic mouse line used by Ren et al appears to functionally impair ependymal cell function compared with mouse lines used in other studies. These differences underscore the challenges in examining NSPCs within in vivo SCI models.…”

“…Indeed, the transgenic mouse line used by Ren et al appears to functionally impair ependymal cell function compared with mouse lines used in other studies. 47 These differences underscore the challenges in examining NSPCs within in vivo SCI models. The importance of NSPC-derived myelin to the regeneration of damaged axons after SCI is further borne out by studies using myelindeficient shiverer mutant mice.…”