Regulation of PP2A activity by Mid1 controls cranial neural crest speed and gangliogenesis

Abstract

X-linked Opitz syndrome (XLOS), caused by mutation in the MID1 gene, is a midline malformation syndrome with obvious craniofacial abnormalities. Because cranial neural crest cells (CNC) play a pivotal role in cranial morphogenesis, we examined the spatio-temporal expression of cMid1 in chick embryos and investigated if alterations in Mid1 protein function, specifically the ability of Mid1 to negatively regulate levels of protein phosphatase 2A (PP2A), affected CNC survival or migration. During the main phase of CNC migration (stage 9 to 11) cMid1 is strongly expressed within r2 and a subset of CNC in cranial mesenchyme at the level of r1/2 to the isthmus, but is not expressed in more caudal CNC streams. Inhibiting cMid1 function in r2 elevated PP2A levels. Overexpression of PP2A in r2 slowed CNC migration in vitro and in ovo and inhibited trigeminal gangliogenesis. Conversely in r4, forced expression of cMid1, or pharmacological inhibition of PP2A lowered PP2A levels. Inhibition of PP2A in r4 CNC in vitro up-regulated the disintegrin and metalloprotease ADAM10 and selectively increased CNC motility on fibronectin and collagen substrates, but not on laminin. In ovo, inhibiting PP2A activity in r4 increased CNC migration and hastened formation of the geniculate/vestibuloacoustic ganglion, comprising mostly epibranchial placode neuroblasts. Placodal neuroblast migration into the cranial mesenchyme is known to depend on the presence of r4 CNC and we show that inhibition of PP2A in r4 CNC causes premature breakdown of the epibranchial placode basement membrane and early immigration of placodal neuroblasts. In all cases, CNC proliferation and death were unaffected by altered PP2A levels. We propose that factors capable of altering PP2A activity, such as Mid1, affect CNC motility and matrix remodeling, thereby modulating craniofacial development.

Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

“…Again the effect was more pronounced in the AR-positive cells. It was recently reported that activation of PP2A via inhibition of MID1 reduced the migration of neural crest cells [33]. Metformin might mediate a similar effect in AR negative and positive prostate cancer cells in addition to its ability to downregulate AR.…”

Neural crest and placode interaction during the development of the cranial sensory system

“…Inhibition of MID1, a regulator of PP2A that is expressed in the neural crest, results in delayed neural crest migration and an inhibition of trigeminal gangliogesis (Latta and Golding, 2012). In contrast, overexpression of MID1 or inhibition of PP2A, leads to increased neural crest migration and placodal cells delaminate prematurely (Latta and Golding, 2012). Together, these results suggest that the neural crest produce a signal to trigger the delamination of placodal cells.…”

Paladin is an antiphosphatase that regulates neural crest cell formation and migration

“…A growing list of kinases active in neural crest cells (for example Banerjee et al, 2011; Jin et al, 2012; Murphy et al, 2011; Ossipova and Sokol, 2011) reinforces the idea that phosphorylation is important for neural crest development. Meanwhile, mutation of the phosphatase Shp2 was recently shown to cause abnormalities in neural crest derivatives (Nakamura et al, 2009; Stewart et al, 2010) while inhibition of PP2A phosphatase activity results in increased cranial neural crest migration (Latta and Golding, 2012). While target protein phosphorylation status can determine biological activity, for example phosphorylation of the neural crest transcription factor Twist affects binding partner choice and transcriptional outcome (Firulli and Conway, 2008), a neural crest antiphosphatase that can sustain target phosphorylation has never been described.…”