About

Jan L. Christian, PhD, is a faculty member at the Spencer Fox Eccles School of Medicine, specializing in neurobiology. His research program focuses on cell-cell signaling molecules such as bone morphogenetic proteins (BMPs) and nodals, which are critical in specifying cell fate during vertebrate embryogenesis. His work aims to understand how BMP activity is regulated through cleavage of the precursor protein and interactions with the extracellular matrix, utilizing targeted mutagenesis in mice and cell biological approaches in Xenopus embryos. Additionally, he studies how mutations within the BMP4 prodomain, associated with congenital birth defects in humans, impact BMP dimer formation and function. Christian's research also includes analysis of signal transduction downstream of Tril, a transmembrane protein involved in blood and central nervous system formation, as well as immune responses in adults. His contributions have advanced understanding of developmental signaling pathways, BMP activation, and the molecular mechanisms underlying embryonic development and disease.

Research topics

• Biology
• Cell biology
• Genetics
• Chemistry
• Internal medicine

Selected publications

• Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  eLife · 2025-05-19

  articleOpen accessSenior author

  Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4 S91C , or BMP4 E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4 S91C and Bmp4 E93G knock-in mice and found that Bmp4 S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4 E93G/E93G mice die before weaning and Bmp4 −/E93G mutants die prenatally with reduced or absent eyes, heart, and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4 S91C and Bmp4 E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.

  PublisherDOI

• Author response: Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  2025-05-29

  peer-reviewOpen accessSenior author
  PublisherDOI

• Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  eLife · 2025-01-16 · 3 citations

  articleOpen accessSenior author

  Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4 S91C , or BMP4 E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4 S91C and Bmp4 E93G knock-in mice and found that Bmp4 S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4 E93G/E93G mice die before weaning and Bmp4 −/E93G mutants die prenatally with reduced or absent eyes, heart, and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4 S91C and Bmp4 E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.

  PublisherOA PDFDOI

• Author response: Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  2025-04-02

  peer-reviewOpen accessSenior author

  Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4S91C or BMP4E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4S91C and Bmp4E93Gknock-in mice and found that Bmp4S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4E93G/E93G mice die before weaning and Bmp4−/E93Gmutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4S91C and Bmp4E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.Mutations associated with birth defects in humans that prevent phosphorylation of the BMP4 prodomain preclude proteolytic activation of the precursor protein

  PublisherDOI

• MuSK Regulates Neuromuscular Junction Nav1.4 Localization and Excitability

  Journal of Neuroscience · 2025-01-29 · 4 citations

  articleOpen access

  The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the NMJ transduces nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires cholinergic signaling, which generates endplate potentials (EPPs), and excitation, the amplification of an EPP by postsynaptic voltage-gated sodium channels (Nav1.4) to generate the MFAP. Compared to the cholinergic component, the signaling pathways that organize Nav1.4 are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as the main organizer of acetylcholine receptors (AChRs), also binds BMPs via its Ig3 domain and shapes BMP-induced signaling. Using mice lacking the MuSK Ig3 domain ("ΔIg3-MuSK"), we probed the role of this domain at the NMJ. NMJs formed in ΔIg3-MuSK animals with pre- and postsynaptic specializations aligned at all ages examined. However, the ΔIg3-MuSK postsynaptic apparatus was fragmented from an early age. Synaptic electrophysiology showed that spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable at WT and ΔIg3-MuSK NMJs. However, single fiber electromyography revealed that nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal, exhibiting jitter and blocking. Nerve-evoked compound muscle action potentials and muscle force were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK NMJs, but not extrasynaptically, indicating that the observed excitability defects result from impaired synaptic localization of this ion channel. We propose distinct, domain-specific roles for MuSK at the NMJ: the Ig1 domain mediates agrin-LRP4-mediated AChR localization, while the Ig3 domain maintains postsynaptic Nav1.4 density, conferring the muscle excitability required to amplify cholinergic signals and trigger action potentials.

  PublisherOA PDFDOI

• Author response: Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  2025-05-09

  peer-reviewOpen accessSenior author

  Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4S91C or BMP4E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4S91C and Bmp4E93Gknock-in mice and found that Bmp4S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4E93G/E93G mice die before weaning and Bmp4-/E93Gmutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4S91C and Bmp4E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.Mutations associated with birth defects in humans that prevent phosphorylation of the BMP4 prodomain preclude proteolytic activation of the precursor protein

  PublisherDOI

• Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  eLife · 2025-04-02

  preprintOpen accessSenior author

  Abstract Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4S91C or BMP4E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4S91C and Bmp4E93Gknock-in mice and found that Bmp4S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4E93G/E93G mice die before weaning and Bmp4−/E93Gmutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4S91C and Bmp4E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.

  PublisherDOI

• Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  eLife · 2025-05-09

  preprintOpen accessSenior author

  Abstract Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4S91C or BMP4E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4S91C and Bmp4E93Gknock-in mice and found that Bmp4S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4E93G/E93G mice die before weaning and Bmp4-/E93Gmutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4S91C and Bmp4E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.

  PublisherDOI

• Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to early lethality in mice

  eLife · 2025-01-16

  preprintOpen accessSenior author

  Abstract Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either as a homodimer, or as a more active BMP4/7 heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of BMP4 homodimers or heterodimers generated from BMP4, BMP4S91C or BMP4E93G precursor proteins in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not heterodimers. We generated Bmp4S91Cand Bmp4E93G knock-in mice and found that Bmp4S91C/S91Cmice die by E11.5 and display reduced BMP activity in multiple tissues including the heart at E10.5. Most Bmp4E93G/E93G mice die before weaning and Bmp4-/E93G mutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4S91C and Bmp4E93Gembryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of cleaved ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers.

  PublisherDOI

• Mutations that prevent phosphorylation of the BMP4 prodomain impair proteolytic maturation of homodimers leading to lethality in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-09 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Bone morphogenetic protein4 (BMP4) plays numerous roles during embryogenesis and can signal either alone as a homodimer, or together with BMP7 as a more active heterodimer. BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments. In humans, heterozygous mutations within the prodomain of BMP4 are associated with birth defects. We studied the effect of two of these mutations (p.S91C and p.E93G), which disrupt a conserved FAM20C phosphorylation motif, on ligand activity. We compared the activity of ligands generated from BMP4, BMP4 S91C or BMP4 E93G in Xenopus embryos and found that these mutations reduce the activity of BMP4 homodimers but not BMP4/7 heterodimers. We generated Bmp4 S91C and Bmp4 E93G knock-in mice and found that Bmp4 S91C/S91C mice die by E11.5 and display reduced BMP activity in multiple tissues including the heart. Most Bmp4 E93G/E93G mice die before weaning and Bmp4 -/E93G mutants die prenatally with reduced or absent eyes, heart and ventral body wall closure defects. Mouse embryonic fibroblasts (MEFs) isolated from Bmp4 S91C and Bmp4 E93G embryos show accumulation of BMP4 precursor protein, reduced levels of cleaved BMP ligand and reduced BMP activity relative to MEFs from wild type littermates. Because Bmp7 is not expressed in MEFs, the accumulation of unprocessed BMP4 precursor protein in mice carrying these mutations most likely reflects an inability to cleave BMP4 homodimers, leading to reduced levels of ligand and BMP activity in vivo. Our results suggest that phosphorylation of the BMP4 prodomain is required for proteolytic activation of BMP4 homodimers, but not heterodimers. Summary Statement Mutations associated with birth defects in humans that prevent phosphorylation of the BMP4 prodomain preclude proteolytic activation of the precursor protein

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HD042598

  NIH · $2.2M · 2009

• NIH Grant R01HD037976

  NIH · $2.7M · 2014

• NIH Grant R03HD050242

  NIH · $151k · 2008

• NIH Grant T32HD049309

  NIH · $1.8M · 2012

• NIH Grant K02HD001167

  NIH · $365k · 2001

Frequent coauthors

• Randall T. Moon

  16 shared

• Takuya Nakayama

  University of Virginia

  12 shared

• Devorah C. Goldman

  Oregon Health & Science University

  8 shared

• Autumn McKnite

  University of Utah

  7 shared

• Mizuho S. Mimoto

  University of California San Diego Medical Center

  7 shared

• Sylvia Nelsen

  Oregon Health & Science University

  7 shared

• Anup Tilak

  University of Minnesota

  6 shared

• Hyung-Seok Kim

  6 shared