Brandstaetter, A. | Search bioRxiv

bioRxiv2025

Differential microstructural development within sensorimotor cortical regions: A diffusion MRI study in preterm and full-term infants

The sensorimotor system develops early in utero and supports the emergence of body representations critical for perception, action, and interaction with environment. While somatotopic protomaps are already developed in the primary somatosensory and motor cortices in late pregnancy, little is known about the anatomical substrates of this functional specialization. In this study, we aimed to decipher the microstructural properties of these regions in the developing brain. Using advanced diffusion MRI and post-processing tools, we parcellated the pre- and post-central gyri into microstructurally distinct clusters along the lateral-to-medial axis in full-term neonates, confirming the early differentiation within sensorimotor regions. These clusters were further analyzed in preterm infants scanned near birth and at term-equivalent age (TEA), compared with another group of full-term neonates. Applying a multivariate Mahalanobis distance approach, we quantified deviations in preterm cortical microstructure relative to the full-term reference. Preterm infants showed significant region- and position-specific deviations at both ages, though these were smaller at TEA, consistently with ongoing maturation during the pre-term period. Differences between the pre- and post-central gyri, and along the somatotopic axis, suggested differential vulnerability to prematurity. In particular, the motor regions appeared to be at a more advanced stage of maturation close to birth and less vulnerable at TEA than somatosensory regions. An opposite trend was observed for lateral positions related to mouth representation compared with intermediary and medial positions. These findings support the notion that early sensorimotor cortical specialization is microstructurally emergent during gestation and sensitive to atypical developmental context of preterm birth.

neuroscience↗

bioRxiv2024

PHLPP2 is a pseudophosphatase that lost activity in the metazoan ancestor

The phosphoinositide 3-kinase (PI3K) pathway is a major regulator of cell and organismal growth. Consequently, hyperactivation of PI3K and its downstream effector kinase, Akt, is observed in many human cancers. PH domain leucine-rich repeat-containing protein phosphatases (PHLPP), two paralogous members of the metal-dependent protein phosphatase family, have been reported as negative regulators of Akt signaling and, therefore, tumor suppressors. However, the stoichiometry and identity of the bound metal ion(s), mechanism of action, and enzymatic specificity of these proteins are not known. Seeking to fill these gaps in our understanding of PHLPP biology, we unexpectedly discovered that PHLPP2 has no catalytic activity against the regulatory phosphorylation sites of Akt, nor the generic substrate para -nitrophenylphosphate. Instead, we found that PHLPP2 is a pseudophosphatase with a single zinc ion bound in its catalytic center. Furthermore, we found that current cancer genomics data do not support the proposed role of PHLPP1 or PHLPP2 as tumor suppressors. Phylogenetic analyses revealed an ancestral phosphatase that arose more than 1 Mya, but that lost activity at the base of the metazoan lineage. In summary, our results provide a molecular explanation for the inconclusive results that have hampered research on PHLPP and argue for a new focus on non-catalytic roles of PHLPP1 and PHLPP2. Significance StatementPHLPP1 and PHLPP2 have previously been reported as protein phosphatases that specifically inactivate Akt, a pro-growth and survival kinase hyperactivated in many human cancers. Unexpectedly, we found that purified PHLPP2 has no detectable enzymatic activity in vitro, an observation which can be rationalized by its unusual active site, which has diverged significantly from that of canonical metal-dependent phosphatases. Furthermore, we show that cancer genomics do not support a role for either PHLPP1 or PHLPP2 in cancer. Our findings argue for the exploration of alternative hypotheses regarding the role of PHLPP in Akt signaling and cancer, with a focus on its non-catalytic functions.

biochemistry↗