{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:27:10Z","timestamp":1787837230201,"version":"build-2784847793"},"posted":{"date-parts":[[2024,11,24]]},"group-title":"Cell Biology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,24]],"date-time":"2024-11-24T00:00:00Z","timestamp":1732406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,11,24]]},"abstract":"\n The extracellular matrix (ECM) is a mixture of glycoproteins and fibrous proteins that provide the biophysical properties necessary to maintain cellular homeostasis. ECM integrity is of particular importance during development, where it allows proper migration and cellular differentiation. Laminins are ECM heterotrimeric proteins consisting of \u03b1, \u03b2, and \u03b3 chains. There are five known \u03b1 chains, four \u03b2 chains, and three \u03b3 chains. Thus, there are 60 potential combinations for laminin trimers, however only 16 laminin trimers have been identified to date. Furthermore, none of them contain laminin \u03b24 and its function is unknown. Here, we sought to characterize the role of\n LAMB4<\/jats:italic>\n (the gene encoding laminin \u03b24) during human embryonic development of the peripheral sensory nervous system. Using human pluripotent stem cells (hPSCs), we found that\n LAMB4<\/jats:italic>\n is expressed in the ectoderm in the early stages of sensory neuron (SN) specification. SNs, part of the peripheral nervous system, are specialized neurons that detect pain, temperature, and touch. Surprisingly, more than 20 million people in the US have some form of peripheral nerve damage (including SNs), however there are very few treatment options available. Learning about the biology of peripheral neurons will uncover potential new therapeutic targets, thus we focused on understanding the effects of\n LAMB4<\/jats:italic>\n in SNs. First, we knocked out\n LAMB4<\/jats:italic>\n in hPSCs, using CRISPR\/Cas9, and found that loss of\n LAMB4<\/jats:italic>\n impairs the migration of the SN progenitors neural crest cells (NCCs) and harms SN development and survival. To assess if\n LAMB4<\/jats:italic>\n has clinical relevance, we studied the genetic disorder Familial Dysautonomia (FD), which specifically affects the peripheral nervous system. FD is caused by a mutation in\n ELP1<\/jats:italic>\n (a component of the Elongator complex) leading to developmental and degenerative defects in SNs. A previous report showed that patients with severe FD harbor additional single nucleotide variants in LAMB4. We found that these variants sharply downregulate the expression of\n LAMB4<\/jats:italic>\n and laminin \u03b24 levels in SNs differentiated from induced pluripotent stem cells (iPSCs) reprogramed from patients with severe FD. Moreover, a healthy ECM is sufficient to rescue the developmental phenotypes of FD, further confirming that ECM defects contribute significantly to the etiology of FD. Finally, we found that LAMB4\/laminin \u03b24 is necessary for actin filament accumulation and it interacts with laminin \u03b14 and laminin \u03b33, forming the laminin-443, a previously unreported laminin trimer. Together, these results show that\n LAMB4<\/jats:italic>\n is a critical, but largely unknown gene required for SN development and survival.\n <\/jats:p>","DOI":"10.1101\/2024.11.22.624899","type":"posted-content","created":{"date-parts":[[2024,11,24]],"date-time":"2024-11-24T04:40:48Z","timestamp":1732423248000},"source":"Crossref","is-referenced-by-count":2,"title":["Laminin \u03b24 is required for the development of human peripheral sensory neurons"],"prefix":"10.64898","author":[{"given":"Kenyi","family":"Saito-Diaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tripti","family":"Saini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archie Jayesh","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimata Safi","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trinity Nora","family":"Knight","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Beatrice","family":"Gogita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Zeltner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.11.22.624899","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:31:35Z","timestamp":1768462295000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.11.22.624899"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,24]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1101\/2024.11.22.624899","relation":{},"subject":[],"published":{"date-parts":[[2024,11,24]]},"subtype":"preprint"}}