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We used kinome analysis to screen for kinase activity patterns in neural tissues from wildtype (WT) and R6\/2 mice at a pre-symptomatic (e.g., embryonic) and symptomatic (e.g., between 3 and 10\u00a0weeks postnatal) time points. We identified changes in several signaling cascades, for example, the Akt\/FoxO3\/CDK2, mTOR\/ULK1, and RAF\/MEK\/CREB pathways. We also identified the Rho-Rac GTPase cascade that contributes to cytoskeleton organization through modulation of the actin-binding proteins, cofilin and profilin. Immunoblotting revealed higher levels of phosphoSer138-profilin in embryonic R6\/2 mouse samples (cf. WT mice) that diminish progressively and significantly over the postnatal, symptomatic course of the disease. We detected sex- and genotype-dependent patterns in the phosphorylation of actin-regulators such a ROCK2, PAK, LIMK1, cofilin, and SSH1L, yet none of these aligned consistently with the changing levels of phosphoSer138-profilin. This could be reflecting an imbalance in the sequential influences these regulators are known to exert on actin signaling. The translational potential of these observations was inferred from preliminary observations of changes in LIMK-cofilin signaling and loss of neurite integrity in neural stem cells derived from an HD patient (versus a healthy control). Our observations suggest that a pre-symptomatic, neurodevelopmental onset of change in the phosphorylation of Ser138-profilin, potentially downstream of distinct signaling changes in male and female mice, could be contributing to cytoskeletal phenotypes in the R6\/2 mouse model of HD pathology.<\/jats:p>","DOI":"10.1007\/s10571-020-00984-2","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T16:43:35Z","timestamp":1603817015000},"page":"871-888","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Progressive Loss of phosphoSer138-Profilin Aligns with Symptomatic Course in the R6\/2 Mouse Model of Huntington\u2019s Disease: Possible Sex-Dependent Signaling"],"prefix":"10.1007","volume":"42","author":[{"given":"Akanksha","family":"Baharani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Roesler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7283-0212","authenticated-orcid":false,"given":"Darrell D.","family":"Mousseau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"984_CR1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.216317","author":"E Aihara","year":"2018","unstructured":"Aihara E, Medina-Candelaria NM, Hanyu H, Matthis AL, Engevik KA, Gurniak CB, Witke W, Turner JR, Zhang T, Montrose MH (2018) Cell injury triggers actin polymerization to initiate epithelial restitution. 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